5-alkynyl-pyridines

ABSTRACT

The present invention encompasses compounds of general formula (1) 
     
       
         
         
             
             
         
       
     
     wherein
     R 1  to R 4 , m and n are defined as in the specification, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and the use thereof for preparing a medicament having the above-mentioned properties.

The present invention relates to new 5-alkynyl-pyridines of generalformula (1)

wherein the groups R¹ to R⁴, m and n have the meanings given below, theisomers thereof, processes for preparing these alkynyl-pyrimidines andtheir use as medicaments.

BACKGROUND OF THE INVENTION

A number of protein kinases have already proved to be suitable targetmolecules for therapeutic intervention in a variety of indications, e.g.cancer and inflammatory and autoimmune diseases. Since a high percentageof the genes involved in the development of cancer which have beenidentified thus far encode kinases, these enzymes are attractive targetmolecules for the therapy of cancer in particular.

Phosphatidylinositol-3-kinases (PI3-kinases) are a subfamily of thelipid kinases which catalyse the transfer of a phosphate group to the3′-position of the inositol ring of phosphoinositides.

The phosphoinositide 3-kinase (PI3K) pathway is activated in a broadspectrum of human cancers. This may occur either via mutation of PI3Kresulting in activation of the kinase, or indirectly via inactivation ofthe phosphotase and tensin homologue (PTEN) suppressor. In both cases,an activation of the signalling cascade is induced that promotestransformation of cells both in vitro and in vivo. Within the cascade,the PI3K family of enzymes and the kinase mTOR play a pivotal role. ThePI3K family comprises 15 lipid kinases with distinct substratespecificities, expression pattern and modes of regulation. They play animportant role in numerous cell processes such as e.g. cell growth anddifferentiation processes, the control of cytoskeletal changes and theregulation of intracellular transport processes. On the basis of theirin vitro specificity for certain phosphoinositide substrates thePI3-kinases can be divided into different categories. The mammaliantarget of rapamycin (mTOR) is a serine/threonine kinase related to thelipide kinases of the PI3-kinase family. It exists in two complexes,mTORC1 and mTORC2, which are differentially regulated, have distinctsubstrate specificities, and are differentially sensitive to rapamycin.The central role of mTOR in controlling key cellular growth and survivalpathways has sparked interest in discovering mTOR inhibitors that bindto the ATP site and therefore target both mTORC2 and mTORC1. As aconsequence, inhibition of the PI3K pathway, particularly mediated viaPI3Kα and mTOR, has emerged as an attractive target for cancertherapeutics. play an important role in numerous cell processes such ase.g. cell growth and differentiation processes, the control ofcytoskeletal changes and the regulation of intracellular transportprocesses. On the basis of their in vitro specificity for certainphosphoinositide substrates the PI3-kinases can be divided intodifferent categories.

5-Alkynyl-pyrimidines are described for example as protein kinasesinhibiting compounds in WO2006044823.

DETAILED DESCRIPTION OF THE INVENTION

It has now surprisingly been found that compounds of general formula(1), wherein the groups R¹ to R⁴, m and n have the meanings given below,act as inhibitors of kinases. Thus, the compounds according to theinvention may be used for example for the treatment of diseasesconnected with the activity of kinases and characterised by excessive orabnormal cell proliferation.

The present invention relates to compounds of general formula (1)

wherein

R¹ and R⁴ independently from one another denotes a group selected fromamong R^(a), R^(b) and R^(a) substituted by one or more identical ordifferent R^(b) and/or R^(c); or

one R¹ together with the pyridine form a 9-10 membered heteroaryl ring,which is optionally substituted with one or more identical or differentR^(b) and/or R^(c); and

R² and R³ independently from one another denotes a group selected fromamong C₁₋₆alkyl, C₃₋₈cycloalkyl, 3-8 membered heterocycloalkyl,C₆₋₁₀aryl and 5-12 membered heteroaryl, optionally substituted by one ormore identical or different R⁵ and

each R⁵ denotes a group selected from among R^(a), R^(b) and R^(a)substituted by one or more identical or different R^(b) and/or R^(c);and

each R^(a) independently of one another denotes a group optionallysubstituted by one or more identical or different R^(b) and/or R^(c),selected from among C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl,

each R^(b) denotes a suitable group and is selected independently of oneanother from among ═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(c),═NR^(c), ═NOR^(c), ═NNR^(c)R^(c), ═NN(R^(g))C(O)NR^(c)R^(c),—NR^(c)R^(c), —ONR^(c)R^(c), —N(OR^(c))R^(c), —N(R^(g))NR^(c)R^(c),halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(c),—S(O)OR^(c), —S(O)₂R^(c), —S(O)₂OR^(c), —S(O)NR^(c)R^(c),—S(O)₂NR^(c)R^(c), —S(O)R^(c), —OS(O)₂R^(c), —OS(O)₂OR^(c),—OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(c), —C(O)OR^(c),—C(O)SR^(c), —C(O)NR^(c)R^(c), —C(O)N(R^(g))NR^(c)R^(c),—C(O)N(R^(g))OR^(c), —C(NR^(g))NR^(c)R^(c), —C(NOH)R^(c),—C(NOH)NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c), —OC(O)SR^(c),—OC(O)NR^(c)R^(c), —OC(NR^(g))NR^(c)R^(c), —SC(O)R^(c), —SC(O)OR^(c),—SC(O)NR^(c)R^(c), —SC(NR^(g))NR^(c)R^(c), —N(R^(g))C(O)R^(c),—N[C(O)R^(c)]₂, —N(OR^(g))C(O)R^(c), —N(R^(g))C(NR^(g))R^(c),—N(R^(g))N(R^(g))C(O)R^(c), —N[C(O)R^(c)]NR^(c)R^(c),—N(R^(g))C(S)R^(c), —N(R^(g))S(O)R^(c), —N(R^(g))S(O)OR^(c),—N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)]₂, —N(R^(g))S(O)₂OR^(c),—N(R^(g))S(O)₂NR^(c)R^(c), —N(R^(g))[S(O)₂]₂R^(c), —N(R^(g))C(O)OR^(c),—N(R^(g))C(O)SR^(c), —N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(O)NR^(g)NR^(c)R^(c), —N(R^(g))N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(S)NR^(c)R^(c), —[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c),—N{[C(O)]₂R^(c)}₂, —N(R^(g))[C(O)]₂OR^(c), —N(R^(g))[C(O)]₂NR^(c)R^(c),—N{[C(O)]₂OR^(c)}₂, —N {[C(O)]₂NR^(c)R^(c)}₂, —[N(R^(g))C(O)]₂OR^(c),—N(R^(g))C(NR^(g))OR^(c), —N(R^(g))C(NOH)R^(c),—N(R^(g))C(NR^(g))SR^(c), —N(R^(g))C(NR^(g))NR^(c)R^(c) and—N═C(R^(g))NR^(c)R^(c) and

each R^(c) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(d)and/or R^(e), selected from among C₁₋₆alkyl, 2-6 membered heteroalkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 5-12 membered hetero-aryl, 6-18 memberedheteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 memberedheterocycloalkylalkyl, and

each R^(d) denotes a suitable group and is selected independently of oneanother from among ═O, —OR^(e), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(e),═NR^(e), ═NOR^(e), ═NNR^(e)R^(e), ═NN(R^(g))C(O)NR^(e)R^(e),—NR^(e)R^(e), —ONR^(e)R^(e), —N(R^(g))NR^(e)R^(e), halogen, —CF₃, —CN,—NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(e), —S(O)OR^(e),—S(O)₂R^(e), —S(O)₂OR^(e), —S(O)NR^(e)R^(e), —S(O)₂NR^(e)R^(e),—OS(O)R^(e), —OS(O)₂R^(e), —OS(O)₂OR^(e), —OS(O)NR^(e)R^(e),—OS(O)₂NR^(e)R^(e), —C(O)R^(e), —C(O)OR^(e), —C(O)SR^(e),—C(O)NR^(e)R^(e), —C(O)N(R^(g))NR^(e)R^(e), —C(O)N(R^(g))OR^(e),—C(NR^(g))NR^(e)R^(e), —C(NOH)R^(e), —C(NOH)NR^(e)R^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)SR^(e), —OC(O)NR^(e)R^(e), —OC(NR^(g))NR^(e)R^(e),—SC(O)R^(e), —SC(O)OR^(e), —SC(O)NR^(e)R^(e), —SC(NR^(g))NR^(e)R^(e),—N(R^(g))C(O)R^(e), —N[C(O)R^(e)]₂, —N(OR^(g))C(O)R^(e),—N(R^(g))C(NR^(g))R^(e), —N(R^(g))N(R^(g))C(O)R^(e),—N[C(O)R^(e)]NR^(e)R^(e), —N(R^(g))C(S)R^(e), —N(R^(g))S(O)R^(e),—N(R^(g))S(O)OR^(e)—N(R^(g))S(O)₂R^(e), —N[S(O)₂R^(e)]₂,—N(R^(g))S(O)₂OR^(e), —N(R^(g))S(O)₂NR^(e)R^(e), —N(R^(g))[S(O)₂]₂R^(e),—N(R^(g))C(O)OR^(e), —N(R^(g))C(O)SR^(e), —N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(O)NR^(g)NR^(e)R^(e), —N(R^(g))N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(S)NR^(e)R^(e), —[N(R^(g))C(O)]₂R^(e), —N(R^(g))[C(O)]₂R^(e),—N{[C(O)]₂R^(e)}₂, —N(R^(g))[C(O)]₂OR^(e), —N(R^(g))[C(O)]₂NR^(e)R^(e),—N{[C(O)]₂OR^(e)}₂, —N{[C(O)]₂NR^(e)R^(e)}₂, —[N(R^(g))C(O)]₂OR^(e),—N(R^(g))C(NR^(g))OR^(e), —N(R^(g))C(NOH)R^(e), —N(R^(g))C(NR^(g))SR^(e), —N(R^(g))C(NR^(g))NR^(e)R^(e) and —N═C(R^(g))NR^(e)R^(e)

each R^(e) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(f)and/or R^(g), selected from among C₁₋₆alkyl, 2-6 membered heteroalkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 5-12 membered hetero-aryl, 6-18 memberedheteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 memberedheterocycloalkylalkyl, and

each R^(f) denotes a suitable group and in each case is selectedindependently of one another from among ═O, —OR^(g), C₁₋₃haloalkyloxy,—OCF₃, ═S, —SR^(g), ═NR^(g), ═NOR^(g), ═NNR^(g)R^(g),═NN(R^(h))C(O)NR^(g)R^(g), —NR^(g)R^(g), —ONR^(g)R^(g),—N(R^(h))NR^(g)R^(g), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(g), —S(O)OR^(g), —S(O)₂R^(g), —S(O)₂OR^(g),—S(O)NR^(g)R^(g), —S(O)₂NR^(g)R^(g), —OS(O)R^(g), —OS(O)₂R^(g),—OS(O)₂OR^(g), —OS(O)NR^(g)R^(g), —OS(O)₂NR^(g)R^(g), —C(O)R^(g),—C(O)OR^(g), —C(O)SR^(g), —C(O)NR^(g)R^(g), —C(O)N(R^(h))NR^(g)R^(g),—C(O)N(R^(h))OR^(g), —C(NR^(h))NR^(g)R^(g), —C(NOH)R^(g),—C(NOH)NR^(g)R^(g), —OC(O)R^(g), —OC(O)OR^(g), —OC(O)SR^(g),—OC(O)NR^(g)R^(g), —OC(NR^(h))NR^(g)R^(g), —SC(O)R^(g), —SC(O)OR^(g),—SC(O)NR^(g)R^(g), —SC(NR^(h))NR^(g)R^(g), —N(R^(h))C(O)R^(g),—N[C(O)R^(g)]₂, —N(OR^(h))C(O)R^(g), —N(R^(h))C(NR^(h))R^(g),—N(R^(h))N(R^(h))C(O)R^(g), —N[C(O)R^(g)]NR^(g)R^(g),—N(R^(h))C(S)R^(g), —N(R^(h))S(O)R^(g), —N(R^(h))S(O)OR^(g),—N(R^(h))S(O)₂R^(g), —N[S(O)₂R^(g)]₂, —N(R^(h))S(O)₂OR^(g),—N(R^(h))S(O)₂NR^(g)R^(g), —N(R^(h))[S(O)₂]₂R^(g), —N(R^(h))C(O)OR^(g),—N(R^(h))C(O)SR^(g), —N(R^(h))C(O)NR^(g)R^(g),—N(R^(h))C(O)NR^(h)NR^(g)R^(g), —N(R^(h))N(R^(h))C(O)NR^(g)R^(g),—N(R^(h))C(S)NR^(g)R^(g), —[N(R^(h))C(O)]₂R^(g), —N(R^(h))[C(O)]₂R^(g),—N{[C(O)]₂R^(g)}₂, —N(R^(h))[C(O)]₂OR^(g), —N(R^(h))[C(O)]₂NR^(g)R^(g),—N{[C(O)]₂OR^(g)}₂, —N{[C(O)]₂NR^(g)R^(g)}₂, —[N(R^(h))C(O)]₂OR^(g),—N(R^(h))C(NR^(h))OR^(g), —N(R^(h))C(NOH)R^(g),—N(R^(h))C(NR^(h))SR^(g), —N(R^(h))C(NR^(h))NR^(g)R^(g); and—N═C(R^(h))NR^(h)R^(h); and

each R^(g) independently of one another denotes hydrogen or a groupoptionally substituted by one or more identical or different R^(h),selected from among C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12membered hetero-aryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl; and

each R^(h) is selected independently of one another from among hydrogen,C₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 memberedheteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl; and

m denotes 0, 1 or 2; and

n denotes 0, 1, 2 or 3; and

optionally in the form of the prodrugs, the tautomers, the racemates,the enantiomers, the diastereomers, the prodrugs and the mixturesthereof, and optionally the pharmacologically acceptable salts thereof.

One aspect of the invention relates to compounds of general formula (1),wherein R³ denotes C₆₋₁₀aryl or 5-12 membered Heteroaryl, optionallysubstituted by one or more identical or different R⁵.

Another aspect of the invention relates to compounds of general formula(1), wherein R³ denotes phenyl, optionally substituted by one or moreidentical or different R⁵.

Another aspect of the invention relates to compounds of general formula(1), wherein R³ denotes pyridyl, optionally substituted by one or moreidentical or different R⁵.

Another aspect of the invention relates to compounds of general formula(1), wherein R³ denotes pyrazolyl, optionally substituted by one or moreidentical or different R⁵.

Another aspect of the invention relates to compounds of general formula(1), wherein R² denotes methyl or ethyl.

Another aspect of the invention relates to compounds of general formula(1), wherein n denotes 1 or 2.

Another aspect of the invention relates to compounds of general formula(1), wherein R¹ denotes methyl, ethyl or —NR^(c)R^(c).

Another aspect of the invention relates to compounds of general formula(1), wherein R¹ is selected from —NH₂, —NH—CH₃ and —N(CH₃)₂.

Another aspect of the invention relates to compounds of general formula(1), wherein R^(a) is selected from hydrogen, methyl, ethyl andcyclopropyl.

Another aspect of the invention relates to compounds of general formula(1), wherein R^(b) is selected from —F, —Cl, —CH₃, —OCH₃, —CF₃,—C(O)—R^(c), —C(O)NR^(c)R^(c), —C(O)OH, —C(O)OCH₃, —C(O)—NH₂,—C(O)—NHCH₃, —C(O)—N(CH₃)₂, —S(O)₂CH₃, -2-propyl-R^(c).

Another aspect of the invention relates to compounds of general formula(1), wherein R^(c) is selected from —H, —CN, -methyl, -ethyl,—(CH₂)₂—OCH₃, piperazinyl, piperidinyl, pyrrolidinyl and morpholinyl.

Another aspect of the invention relates to compounds of general formula(1), wherein R³ is phenyl substituted with one or more R⁵, wherein atleast one of R⁵ is —C(O)R^(C) and wherein R^(c) is

Another aspect of the invention relates to compounds of general formula(1), wherein R^(d) is selected from —H, -methyl, -ethyl, -propyl, —OH,—OCH₃, and —C(O)CH₃.

Another aspect of the invention relates to compounds of general formula(1), wherein R^(e) is selected from -cyclopropyl, cyclopentyl, oxiranyl,tetrahydropyranyl, and morpholinyl.

Another aspect of the invention relates to compounds of general formula(1), wherein R³ is selected from the group consisting of:

One aspect of the invention relates to compounds of general formula (1),or the pharmacologically effective salts thereof, as medicaments.

One aspect of the invention relates to compounds of general formula (1),or the pharmacologically effective salts thereof, for preparing amedicament with an antiproliferative activity.

One aspect of the invention is a pharmaceutical preparations, containingas active substance one or more compounds of general formula (1), or thepharmacologically effective salts thereof, optionally in combinationwith conventional excipients and/or carriers.

One aspect of the invention is the use of compounds of general formula(1) for preparing a medicament for the treatment and/or prevention ofcancer, infections, inflammatory and autoimmune diseases.

One aspect of the invention is a pharmaceutical preparation comprising acompound of general formula (1) and at least one other cytostatic orcytotoxic active substance, different from formula (1), optionally inthe form of the tautomers, the racemates, the enantiomers, thediastereomers and the mixtures thereof, as well as optionally thepharmacologically acceptable salts thereof.

DEFINITIONS

As used herein the following definitions apply, unless stated otherwise.

By alkyl substituents are meant in each case saturated, unsaturated,straight-chain or branched aliphatic hydrocarbon groups (alkyl group)and this includes both saturated alkyl groups and unsaturated alkenyland alkynyl groups. Alkenyl substituents are in each case straight-chainor branched, unsaturated alkyl groups, which have at least one doublebond. By alkynyl substituents are meant in each case straight-chain orbranched, unsaturated alkyl groups, which have at least one triple bond.

The term heteroalkyl refers to groups which can be derived from alkyl asdefined above in its broadest sense by replacing one or more of thegroups —CH₃ in the hydrocarbon chains independently of one another bythe groups —OH, —SH or —NH₂, one or more of the groups —CH₂—independently of one another by the groups —O—, —S— or —NH—, one or moreof the groups

by the group

one or more of the groups ═CH— by the group ═N—, one or more of thegroups ═CH₂ by the group ═NH or one or more of the groups ≡CH by thegroup ≡N, while in all only a maximum of three heteroatoms may bepresent in a heteroalkyl, there must be at least one carbon atom betweentwo oxygen and between two sulphur atoms or between one oxygen and onesulphur atom and the group as a whole must have chemical stability.

It flows from the indirect definition/derivation from alkyl thatheteroalkyl is made up of the sub-groups of saturated hydrocarbon chainswith hetero-atom(s), heteroalkenyl and heteroalkynyl, while furthersubdivision into straight-chain (unbranched) and branched may be carriedout. If a heteroalkyl is supposed to be substituted, the substitutionmay take place independently of one another, in each case mono- orpolysubstituted, at all the hydrogen-carrying oxygen, sulphur, nitrogenand/or carbon atoms. Heteroalkyl itself may be linked to the molecule assubstituent both through a carbon atom and through a heteroatom.

By way of example, the following representative compounds are listed:dimethylaminomethyl; dimethylaminoethyl (1-dimethylaminoethyl;2-dimethylaminoethyl); dimethylaminopropyl (1-dimethylaminopropyl,2-dimethylaminopropyl, 3-dimethylaminopropyl); diethylaminomethyl;diethylaminoethyl (1-diethylaminoethyl, 2-diethylaminoethyl);diethylaminopropyl (1-diethylaminopropyl, 2-diethylamino-propyl,3-diethylaminopropyl); diisopropylaminoethyl (1-diisopropylaminoethyl,2-diisopropylaminoethyl); bis-2-methoxyethylamino;[2-(dimethylamino-ethyl)-ethyl-amino]-methyl;3-[2-(dimethylamino-ethyl)-ethyl-amino]-propyl; hydroxymethyl;2-hydroxyethyl; 3-hydroxypropyl; methoxy; ethoxy; propoxy;methoxymethyl; 2-methoxyethyl etc.

Haloalkyl relates to alkyl groups, wherein one or more hydrogen atomsare replaced by halogen atoms. Haloalkyl includes both saturated alkylgroups and unsaturated alkenyl and alkynyl groups, such as for example—CF₃, —CHF₂, —CH₂F, —CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃,—CF₂CF₂CF₃, —CF₂CH₂CH₃, —CF═CF₂, —CCl═CH₂, —CBr═CH₂, —CI═CH₂, —C≡C—CF₃,—CHFCH₂CH₃ and —CHFCH₂CF₃.

Halogen refers to fluorine, chlorine, bromine and/or iodine atoms.

By cycloalkyl is meant a mono or bicyclic ring, while the ring systemmay be a saturated ring or, however, an unsaturated, non-aromatic ring,which may optionally also contain double bonds, such as for examplecyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl and norbornenyl.

Cycloalkylalkyl includes a non-cyclic alkyl group wherein a hydrogenatom bound to a carbon atom, usually to a terminal C atom, is replacedby a cycloalkyl group.

Aryl relates to monocyclic or bicyclic aromatic rings with 6-10 carbonatoms such as phenyl and naphthyl, for example.

Arylalkyl includes a non-cyclic alkyl group wherein a hydrogen atombound to a carbon atom, usually to a terminal C atom, is replaced by anaryl group.

By heteroaryl are meant mono- or bicyclic aromatic rings, which insteadof one or more carbon atoms contain one or more, identical or differenthetero atoms, such as e.g. nitrogen, sulphur or oxygen atoms. Examplesinclude furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl,thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl.Examples of bicyclic heteroaryl groups are indolyl, isoindolyl,benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolyl, benzopyrazolyl, indazolyl,isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl,quinazolinyl and benzotriazinyl, indolizinyl, oxazolopyridyl,imidazopyridyl, naphthyridinyl, indolinyl, isochromanyl, chromanyl,tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuryl,isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridyl,benzotetrahydrofuryl, benzotetrahydrothienyl, purinyl, benzodioxolyl,triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl,imidazopyridyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl,benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridyl-N-oxidetetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl-N-oxide,pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide,quinolinyl-N-oxide, indolyl-N-oxide, indolinyl-N-oxide,isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide,phthalazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide,oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-N-oxide,indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide,pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide,triazolyl-N-oxide, tetrazolyl-N-oxide, benzothiopyranyl-5-oxide andbenzothiopyranyl-S,S-dioxide.

Heteroarylalkyl encompasses a non-cyclic alkyl group wherein a hydrogenatom bound to a carbon atom, usually to a terminal C atom, is replacedby a heteroaryl group.

Heterocycloalkyl relates to saturated or unsaturated, non-aromaticmono-, bicyclic or bridged bicyclic rings comprising 3-12 carbon atoms,which instead of one or more carbon atoms carry heteroatoms, such asnitrogen, oxygen or sulphur. Examples of such heterocyloalkyl groups aretetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl,isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl,homopiperidinyl, homopiperazinyl, homothiomorpholinyl,thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, tetrahydropyranyl,tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl,dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide,homothiomorpholinyl-S-oxide, 2-oxa-5-azabicyclo[2,2,1]heptane,8-oxa-3-aza-bicyclo[3.2.1]octane, 3.8-diaza-bicyclo[3.2.1]octane,2,5-diaza-bicyclo[2.2.1]heptane, 3.8-diaza-bicyclo[3.2.1]octane,3.9-diaza-bicyclo[4.2.1]nonane and 2.6-diaza-bicyclo[3.2.2]nonane.

Heterocycloalkylalkyl relates to a non-cyclic alkyl group wherein ahydrogen atom bound to a carbon atom, usually to a terminal C atom, isreplaced by a heterocycloalkyl group.

The following Examples illustrate the present invention withoutrestricting its scope.

General Procedure GP1 Sonogashira Reaction

The halide (1.0 eq.) is dissolved in DMF or THF and PdCl₂(PPh₃)₂ (0.1eq.) and CuI (0.1 eq.) are added. Subsequently, triethylamine (10.0 eq.)and finally the alkyne (1.5 eq.) are added and the reaction mixture isstiffed at 55-65° C. The reaction is monitored by LC-MS. If the iodideis not completed converted after 4 h, additional amounts of alkyne areadded in small portions.

General Procedure GP2 Desilylation of Alkynes

The TMS-alkyne (1.0 eq.) is dissovled in MeOH, K₂CO₃ (0.5 eq.) is addedin one portion and the reaction mixture is stirred at room temperatureuntil conversion is complete (3-16 h). The solvent is removed in vaccuo,the crude product is dissolved in ethyl acetate and the organic phase isextracted with water. The organic phase is dried over MgSO₄, filteredoff and the solvent removed in vaccuo. The product is either usedwithout further purification or purified by chromatography on silica gelusing DCM/MeOH or (cyclo-) hexane/ethyl acetate.

General Procedure GP3 Suzuki Coupling

The 4-chloropyridine (1.0 eq.) is taken up in dioxane, boronic acid (2.0eq.), K₃PO₄ (1.2 eq.), Pd₂(dba)₃ (0.1 eq.) andDicyclohexyl(2′,4′,6′-thisopropylbiphenyl-2-yl)phosphane (“X-Phos”, 0.3eq.) are added and the reaction mixture is stirred either for 3-16 hunder reflux or alternatively for 60-180 min at 150° C. under microwaveradiation. In case the conversion of the starting material is notcomplete, additional amounts of boronic acid and Pd-catalyst are addedand the reaction is re-run.

General Procedure GP4 Saponification of Esters

The ester is taken up in either THF or dioxane, 1.0-2.0 eq. of 1 N NaOHare added and the mixture is heated under reflux until reaction controlshows complete conversion of the starting material. The product eitherprecipitates from the reaction mixture (e.g. after acidification) and isused without additional purification steps or can further be purified bychromatography.

General Procedure 5 (GP5) Amide Formation with Amines

To a mixture of 0.21 mmol starting material, 0.31 mmol TBTU or HATU and0.42 mmol Huenig's base in 2 mL DMSO or THF or NMP is stirred for 5 min.0.31 mmol of amine is added and the resultant mixture is stirred at RTover night. Purification is performed via preparative RP-HPLC orchromatography on silica gel yielding after evaporation of the solventthe desired product.

General Procedure 6 (GP6) Amide Formation with Acid Chlorides

To a mixture of 0.13 mmol of starting material and 67 μL Huenig's basein 2 mL THF is added 0.26 mmol acid chloride. The reaction mixture isstirred over night at RT. The solvent is evaporated and the residue istaken up in 1 mL DMSO insoluble material is filtered off and theresulting solution is purified via preparative RP-HPLC or chromatographyon silica gel yielding after evaporation of the solvent the desiredproduct.

General Procedure 7 (GP7) Urea Formation with Isocyanates

To a mixture of 0.16 mmol of starting material and 64.4 μL Huenig's basein 2 mL THF is added 0.49 mmol isocyanate. The reaction mixture isstirred over night at RT. The solvent is evaporated and the residue istaken up in 1 mL DMSO. Insoluble material is filtered off and theresulting solution is purified via preparative RP-HPLC or chromatographyon silica gel yielding after evaporation of the solvent the desiredproduct.

General Procedure 8 (GP8) Urea Formation Via Pre-Activation of the Amine

To a mixture of 0.34 mmol amine and 0.34 mmol N,N′-carbonyldiimidazoleand 0.34 mmol 1,8-diazabicyclo[5.4.0]undec-7-ene is stirred for 10 minat RT. 0.32 mmol of starting material are added in one portion. Thereaction mixture is heated at 100° C. for 1 h in the microwave. Thesolvent is evaporated and the residue is taken up in 1 mL DMSO,insoluble material is filtered off and the resulting solution ispurified via preparative RP-HPLC or chromatography on silica gelyielding the desired product.

General Procedure 9 (GP9) Amide Formation with Carbonic Acids

To a mixture of 0.62 mmol carbonic acid, 0.93 mmol TBTU and 1.2 mmolHuenig's base in 2 mL DMSO is stiffed for 5 min. 0.31 mmol of startingmaterial is added and the resultant mixture is stirred at RT over night.Purification is performed via preparative RP-HPLC or chromatography onsilica gel yielding after evaporation of the solvent the desiredproduct.

Intermediates A A-1) 5-Iodo-3-trifluoromethyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP1starting from 5.0 g (31 mmol) 3-trifluoro-2-amino pyridine and 6.9 g (31mmol) NIS. Yield after precipitation from the reaction mixture: 6.78 g(76%).

A-2) 2-Methyl-5-trimethylsilanylethynyl-pyridine

The title compound is synthesized according to general procedure GP2starting from 2.0 g (11.6 mmol) 5-bromo-2-methyl-pyridine and 2.3 mL(16.3 mmol) 1-trimethylsilyl-ethyne using 68 mg (0.36 mmol) CuI, 305 mg(1.2 mmol) triphenylphosphine, 213 mg (0.30 mmol) PdCl₂(PPh₃)₂ and 18 mL(127 mmol) triethylamine in 18 mL dry THF. For the work-up the reactionmixture is diluted with ethyl acetate, the organic phase is extractedwith water and brine. The product is purified by chromatography onsilica gel using a hexane/ethyl acetate gradient. Yield: 1.5 g (68%).Note: Sublimation of the product is observed at 40° C./40 mbar.

A-3) 5-Trimethylsilanylethynyl-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP2starting from 5.0 g (28.9 mmol) 5-bromo-2-amino-pyridine and 5.7 mL(40.5 mmol) 1-trimethylsilyl-ethyne using 168 mg (0.88 mmol) CuI, 758 mg(2.9 mmol) triphenylphosphine, 533 mg (0.76 mmol) PdCl₂(PPh₃)₂ and 40 mL(288 mmol) triethylamine in 40 mL dry THF. For the work-up the reactionmixture is diluted with ethyl acetate and small amounts of cyclohexane,the organic phase is extracted with water and brine. The product ispurified by chromatography on silica gel using hexane/ethyl acetate(10/1 v/v). Yield: 5.0 g (91%).

A-4) Methyl-(5-trimethylsilanylethynyl-pyridin-2-yl)-amine

The title compound is synthesized according to general procedure GP2starting from 4.3 g (23.0 mmol) 5-bromo-2-methylamino-pyridine and 4.5mL (32.2 mmol) 1-trimethylsilyl-ethyne using 134 mg (0.71 mmol) CuI, 601mg (2.3 mmol) triphenylphosphine, 420 mg (0.60 mmol) PdCl₂(PPh₃)₂ and 32mL (101 mmol) triethylamine in 40 mL dry THF. For the work-up thereaction mixture is diluted with ethyl acetate and small amounts ofcyclohexane, the organic phase is extracted with water and brine. Theproduct is purified by chromatography on silica gel using a hexane/ethylacetate gradient. Yield: 4.0 g (85%).

Note: Sublimation of the product is observed at 40° C./40 mbar.

A-5) Ethyl-(5-trimethylsilanylethynyl-pyridin-2-yl)-amine

The title compound is synthesized according to general procedure GP2starting from 909 mg (4.5 mmol) 5-bromo-2-ethylamino-pyridine and 0.89mL (6.3 mmol) 1-trimethylsilyl-ethyne using 26 mg (0.13 mmol) CuI, 118mg (0.45 mmol) triphenylphosphine, 82 mg (0.12 mmol) PdCl₂(PPh₃)₂ and6.3 mL (45.0 mmol) triethylamine in 7 mL dry THF. For the work-up thereaction mixture is diluted with ethyl acetate and small amounts ofcyclohexane, the organic phase is extracted with water and brine. Theproduct is purified by chromatography on silica gel using a hexane/ethylacetate gradient.

Yield: 980 mg (99%).

A-6)-5-Trimethylsilanylethynyl-pyridin-3-ol

The title compound is synthesized according to general procedure GP2starting from 2.0 g (11.6 mmol) 5-bromo-3-hydroxy-pyridine and 2.3 mL(16.2 mmol) 1-trimethylsilyl-ethyne using 66 mg (0.3 mmol) CuI, 303 mg(1.2 mmol) triphenylphosphine, 243 mg (0.3 mmol) PdCl₂(PPh₃)₂ and 19 mL(139 mmol) triethylamine in 20 mL dry THF. For the work-up the reactionmixture is diluted with ethyl acetate and small amounts of cyclohexane,the organic phase is extracted with water and brine. The product ispurified by chromatography on silica gel using DCM/MeOH gradient. Yield:2.0 g (91%)

A-7) 5-Trimethylsilanylethynyl-pyridin-3-ylamine

The title compound is synthesized according to general procedure GP2starting from 2.0 g (11.6 mmol) 5-bromo-3-amino-pyridine and 2.3 mL(16.2 mmol) 1-trimethylsilyl-ethyne using 66 mg (0.3 mmol) CuI, 303 mg(1.2 mmol) triphenylphosphine, 243 mg (0.3 mmol) PdCl₂(PPh₃)₂ and 19 mL(139 mmol) triethylamine in 20 mL dry THF. For the work-up the reactionmixture is diluted with ethyl acetate and small amounts of cyclohexane,the organic phase is extracted with water and brine. The product ispurified by chromatography on silica gel using DCM/MeOH gradient. Theproduct precipitated on the column and is subsequently extracted fromthe silica gel with pure MeOH. Yield: 2.0 g (91%).

A-8) 5-Trimethylsilanylethynyl-1H-pyrazolo[3,4-b]pyridine

The title compound is synthesized according to general procedure GP2starting from 1.0 g (5.1 mmol) 5-bromo-1H-pyrazolo[4,5-B]pyridine and1.0 mL (7.1 mmol) 1-trimethylsilyl-ethyne using 29 mg (0.15 mmol) CuI,133 mg (0.51 mmol) triphenylphosphine, 106 mg (0.15 mmol) PdCl₂(PPh₃)₂and 8.4 mL (60.6 mmol) triethylamine in 8 mL dry THF. The formedprecipitate is filtered off and the product is purified by RP-HPLC usingACN/H₂O gradient. Yield: 542 mg (50%)

A-9) 5-Trimethylsilanylethynyl-1H-pyrrolo[2,3-b]pyridine

The title compound is synthesized according to general procedure GP2starting from 3.0 g (15.2 mmol) 5-bromo-1H-pyrrolo[2,3-B]pyridine and3.0 mL (21.3 mmol) 1-trimethylsilyl-ethyne using 87 mg (0.46 mmol) CuI,400 mg (1.5 mmol) triphenylphosphine, 312 mg (0.46 mmol) PdCl₂(PPh₃)₂and 25.4 mL (182 mmol) triethylamine in 25 mL dry THF. The formedprecipitate is filtered off and the product is purified bychromatography on silica gel using a DCM/MeOH gradient. Yield: 3.05 g(94%)

A-10) 6-Trimethylsilanylethynyl-3H-imidazo[4,5-b]pyridine

The title compound is synthesized according to general procedure GP2starting from 1.2 g (6.1 mmol) 5-bromo-3H-imidazo[4,5-B]pyridine and 1.2mL (8.4 mmol) 1-trimethylsilyl-ethyne using 34 mg (0.18 mmol) CuI, 159mg (0.61 mmol) triphenylphosphine, 128 mg (0.18 mmol) PdCl₂(PPh₃)₂ and10.1 mL (72.7 mmol) triethylamine in 10 mL dry THF. The formedprecipitate is filtered off and the product is purified by RP-HPLC usinga ACN/H₂O gradient. Yield: 606 mg (46%)

A-11) 5-Ethynyl-2-methyl-pyridine

The title compound is synthesized according to general procedure GP3starting from 2.2 g (11.6 mmol)2-methyl-5-trimethylsilanylethynyl-pyridine (A4) and 802 mg (5.8 mmol)K₂CO₃ in 13 mL MeOH. The crude product is purified by chromatography onsilica gel using a cyclohexane/ethyl acetate gradient. Since sublimationis observed at 40° C./40 mbar the product is extracted from the organicphase with 1 N HCl and isolated as the hydrochloride afterlyophilization. Yield: 1.3 g (73%).

A-12) 5-Ethynyl-2-amino-pyridine

The title compound is synthesized according to general procedure GP3starting from 5.5 g (28.9 mmol)5-trimethylsilanylethynyl-pyridin-2-ylamine (A5) and 2.0 mg (14.4 mmol)K₂CO₃ in 30 mL MeOH. Yield: 2.89 mg (85%) after chromatography on silicagel.

A-13 (5-Ethynyl-pyridin-2-yl)-methyl-amine

The title compound is synthesized according to general procedure GP3starting from 1.5 g (7.3 mmol)methyl-(5-trimethylsilanylethynyl-pyridin-2-yl)-amine (A6) and 507 mg(3.7 mmol) K₂CO₃ in 10 mL MeOH. Yield: 698 mg (56%) after chromatographyon silica gel.

A-14) (5-Ethynyl-pyridin-2-yl)-ethyl-amine

The title compound is synthesized according to general procedure GP3starting from 980 mg (4.5 mmol) TMS-alkyne and 310 mg (2.3 mmol) K₂CO₃in 6 mL MeOH.

Yield: 388 mg (59%) after chromatography on silica gel.

A-15) 5-Ethynyl-pyridin-3-ol

The title compound is synthesized according to general procedure GP3starting from 2.0 g (10.5 mmol) TMS-alkyne and 722 mg (5.2 mmol) K₂CO₃in 10 mL MeOH. Yield: 804 mg (49%) after chromatography on silica gel.

A-16) 5-Ethynyl-pyridin-3-ylamine

The title compound is synthesized according to general procedure GP3starting from 2.0 g (10.5 mmol) TMS-alkyne and 722 mg (5.2 mmol) K₂CO₃in 10 mL MeOH. Yield: 1.2 g (74%) after chromatography on silica gel andprecipitation from dioxane/HCl.

A-17) 5-Ethynyl-1H-pyrazolo[3,4-b]pyridine

The title compound is synthesized according to general procedure GP3starting from 542 mg (2.5 mmol) TMS-alkyne and 174 mg (1.3 mmol) K₂CO₃in 6 mL MeOH.

Yield: 330 mg (92%) after extraction.

A-18) 5-Ethynyl-1H-pyrrolo[2,3-b]pyridine

The title compound is synthesized according to general procedure GP3starting from 3.05 g (14.2 mmol) TMS-alkyne and 983 mg (7.1 mmol) K₂CO₃in 15 mL MeOH. Yield: 1.23 g (61%) after chromatography on silica gel.

A-19) 6-Ethynyl-3H-imidazo[4,5-b]pyridine

The title compound is synthesized according to general procedure GP3starting from 706 mg (3.3 mmol) TMS-alkyne and 227 mg (1.6 mmol) K₂CO₃in 6 mL MeOH. Yield: 491 mg (94%) after extraction.

A-20) 3-Iodo-2-methyl-pyridin-4-ol

To a solution of 10 g (91.6 mmol) 2-methyl-pyridin-4-ol in 100 mL water20.6 g (91.6 mmol) NIS are added in one portion. The reaction mixture isstirred at RT until reaction control by LC-MS indicated completeconversion of the starting material. The precipitate is filtered off,washed with washed an dried. The isolated solid comprises a mixture ofthe desired product and bis-iodated starting material (presumably4-hydroxy-3,5-diiodo-2-methyl-pyridine) and is used for the next stepwithout further purification.

Yield: 17.6 g.

A-21) 4-Chloro-3-iodo-2-methyl-pyridine

Under an inert atmosphere the crude product obtained from the iodinationis taken up in 300 mL acteonitrile. A solution of 82 g (898 mmol) POCl₃in 50 mL acetonitrile as well as catalytic amounts of P₂O₅ are addedbefore the reaction mixture is heated under reflux for 2 h. LC-MSindicated complete conversion of the starting material. After cooling toRT the mixture is concentrated under vacuum to a volume of about 50 mL.The formed precipitate is filtered off and discarded. The pH of thesolution is adjusted to pH about 1 by addition of KOH (s). Again, theprecipitate is filtered off and discarded. Additional KOH is added untilpH about 7. The product precipitated from the reaction mixture, isfiltered off, washed with water and dried under vacuum at 40° C. Yield:8.1 g (43% over 2 steps).

A-22) 2-Ethyl-pyridine-1-oxide

To the solution 500 g (4.7 mol) 2-ethylpyridine in 2.0 L acetic acid isadded H₂O₂ (1586.0 g, 13.900 mol). Then the mixture is heated to 80° C.overnight. After cooling to room RT, the mixture is poured into thecrushed ice, and extracted with DCM (8×1.0 L). The DCM layers arecombined, washed with saturated Na₂SO₃ solution, dried over anhydrousNa₂SO₄. The solvent is removed in vaccuo to afford the title compound.

Yield: 573.8 g (100%).

A-23) 2-Ethyl-4-nitro-pyridine-1-oxide

Concentrated H₂SO₄ (1826.0 g, 18.660 mol) and fuming HNO₃ (1174.0 g,18.640 mol) are mixed at 0° C. Then 573.8 g (4.7 mol)2-ethyl-pyridine-1-oxide are added to the mixture over 1 h. Theresulting mixture is heated to 80° C. for 3 h. After cooling to RT, themixture is slowly poured into the crushed ice with fierce stirring. Theaqueous layer is extracted with DCM (6×1.0 L), the combined layer isdried over anhydrous Na₂SO₄. The solvent is removed in vaccuo to affordthe title compound. Yield: 700.0 g (89%).

A-24) 2-Ethyl-pyridin-4-ylamine

A solution of 388.0 g (2.3 mol) 2-ethyl-4-nitro-pyridine-1-oxide in 3.0L EtOH and 1.0 L saturated NH₄Cl solution (1.0 L) is stirred with 647.5g (11.6 mol) iron powder. This mixture is refluxed for 3 h. The ironpowder is filtered off with Celite®, and the solvent is removed from thefiltrate in vaccuo to afford a crude oil. This oil is diluted withDCM/MeOH (1.0 L, 10:1) and the undissolved NH₄Cl is removed byfiltration, the filtrate is dried in vaccuo to afford the titlecompound. Yield: 200.0 g (71%).

A-25) 2-Ethyl-pyridin-4-ol

282.1 g (2.3 mol) 2-Ethyl-pyridin-4-ylamine are dissolved inconcentrated HNO₃ (789 mL, 11.561 mol) and H₂O (1.5 L). Then a solutionof NaNO₂ (238.9 g, 3.468 mol) in H₂O (600 mL) is slowly added to thesolution over 2 h at 0° C. After the addition, the mixture is warmed toRT and stirred for additional 2 h. The reaction mixture is stored at −2°C. overnight. The precipitate is collected by filtration, and dried invaccuo to afford the title compound. Yield: 155.1 g, (54%)

A-26) 2-Ethyl-3-iodo-pyridin-4-ol

To a solution of 72.0 g (0.58 mol) 2-ethyl-pyridin-4-ol in 1.0 L H₂O130.0 g (0.58 mol) NIS are added in ten portions over 1 h. The mixtureis stirred at RT overnight. The acetic acid (1.5 L) is added in oneportion. The formed precipitate is removed by filtration. The filtrateis purified on silica gel chromatography (DCM:MeOH about 30:1) to affordthe title compound. Yield: 9.0 g (6%).

A-27) 4-Chloro-2-ethyl-3-iodo-pyridine

A solution of 165.1 g (1.08 mol) POCl₃ in 100 mL CH₃CN is added dropwiseto a solution of 27.1 g (108 mmol) 2-ethyl-3-iodo-pyridin-4-ol in 150 mLCH₃CN at RT. Then Et₃N (21.9 g, 216 mmol) is added slowly over 20 minbefore the reaction mixture is heated to 60° C. for 3 h. The reactionmixture is evaporated in vaccuo to afford an oil. This crude oil ispoured into the crushed ice, and the aqueous phase is extracted withpetroleum ether/EtOAc (3×, 200 mL; 10:1). The organic phase iscollected, dried over anhydrous Na₂SO₄. The solvent is removed in vacuoto afford desired product. Yield: 22.0 g (76%).

A-28) 5-(4-Chloro-2-methyl-pyridin-3-ylethynyl)-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP1starting from 1.0 g (4.0 mmol) 4-chloro-3-iodo-2-methyl-pyridine and 513mg (4.3 mmol) 2-amino-5-ethynyl-pyridine using 75 mg (0.40 mmol) CuI,276 mg (0.40 mmol) PdCl₂(PPh₃)₂ and 5.4 mL (39.5 mmol) triethylamine in40 mL dry DMF. After completion of the reaction the solvent is removedunder vacuum and the product is purified by chromatography on silica gelusing a DCM/MeOH gradient (100:0 to 90:10). Yield: 617 mg (64%).

A-29)[5-(4-Chloro-2-methyl-pyridin-3-ylethynyl)-pyridin-2-yl]-methyl-amine

The title compound is synthesized according to general procedure GP1starting from 20 mg (0.08 mmol) 4-chloro-3-iodo-2-methyl-pyridine and 11mg (0.09 mmol) (5-Ethynyl-pyridin-2-yl)-methyl-amine using 1.5 mg (0.01mmol) CuI, 5.5 mg (0.01 mmol) PdCl₂(PPh₃)₂ and 0.11 mL (0.8 mmol)triethylamine in 1 mL dry DMF. After completion of the reaction theproduct is purified by RP-HPLC using a ACN/H₂O gradient (95:5 to 70:30).Yield: 20 mg (98%).

A-30) 5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP1starting from 1.0 g (3.7 mmol) 4-chloro-3-iodo-2-ethyl-pyridine and 485mg (4.1 mmol) 2-amino-5-ethynyl-pyridine using 36 mg (0.40 mmol) CuI,131 mg (0.40 mmol) PdCl₂(PPh₃)₂ and 5.2 mL (39.5 mmol) triethylamine in25 mL dry DMF. After completion of the reaction the reaction mixture isadded dropwise into water. The precipitate is filtered off and taken upwith iPrOH. The product remains is solution while the side-product(alkyne dimer from Glaser-homo-coupling) forms a precipitate and isfiltered off. The mother liquid is concentrated under vacuum. Yield: 718mg (75%).

A-31)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-methyl-pyridin-4-yl]-2-fluoro-benzoicacid methyl ester

The title compound is synthesized according to general procedure GP3starting from 500 mg (2.1 mmol)5-(4-chloro-2-methyl-pyridin-3-ylethynyl)-pyridin-2-ylamine using 812 mg(4.1 mmol) 3-fluoro-4-methoxycarbonylphenyl boronic acid, 188 mg (0.21mmol) Pd₂(dba)₃, 293 mg (0.62 mmol) X-Phos and 567 mg (2.5 mmol) K₃PO₄in 4 mL dioxane. The reaction mixture is stirred for 180 min at 150° C.under microwave irradiation. The product is purified by chromatographyon silica gel using an DCM/MeOH-gradient (99:1 to 90:10, 20 min) Yield:52 mg (70%).

A-32)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-methyl-pyridin-4-yl]-2-fluoro-benzoicacid

The title compound is synthesized according to general procedure GP4starting from 300 mg (0.83 mmol)4-[3-(6-amino-pyridin-3-ylethynyl)-2-methyl-pyridin-4-yl]-2-fluoro-benzoicacid methyl ester using 0.83 mL (0.83 mmoL) 1 N NaOH in 5 mL THF. Theprecipitate is collected by filtration and washed with THF. Yield: 280mg (97%).

A-33) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-methyl-pyridin-4-yl]-benzoicacid methyl ester

The title compound is synthesized according to general procedure GP3starting from 1.5 g (6.2 mmol)5-(4-chloro-2-methyl-pyridin-3-ylethynyl)-pyridin-2-ylamine using 2.2 g(12.3 mmol) 4-methoxycarbonylphenyl boronic acid, 281 mg (0.31 mmol)Pd₂(dba)₃, 440 mg (0.92 mmol) X-Phos and 1.7 g (7.4 mmol) K₃PO₄ in 25 mLdioxane. The reaction mixture is stirred over night at 100° C. Aftercooling to RT the reaction mixture is added dropwise into water, theprecipitate is filtered off. The solid is taken up in iPrOH, stirred fora few minutes, filtered off and dried under vacuum. Yield: 2.0 g (95%,residual Pd).

A-34) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-methyl-pyridin-4-yl]-benzoicacid

The title compound is synthesized according to general procedure GP4starting from 2.0 g (5.8 mmol)4-[3-(6-amino-pyridin-3-ylethynyl)-2-methyl-pyridin-4-yl]-benzoic acidmethyl ester using 11.6 mL (11.6 mmoL) 1 N NaOH in 8 mL THF. Aftercompletion of the reaction the pH is adjusted to pH about 5 with 1.0 NHCl. The precipitate is collected by filtration, washed with water anddried under vacuum. The solid is taken up in iPrOH, stirred for a fewminutes before the solid is isolated by filtration and dried at 40° C.under vacuum. Yield: 1.9 g (99%).

A-35)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-methyl-pyridin-4-yl]-2-chloro-benzoicacid methyl ester

The title compound is synthesized according to general procedure GP3starting from 300 mg (1.2 mmol)5-(4-chloro-2-methyl-pyridin-3-ylethynyl)-pyridin-2-ylamine using 527 mg(2.4 mmol) 3-chloro-4-methoxycarbonylphenyl boronic acid, 112 mg (0.12mmol) Pd₂(dba)₃, 176 mg (0.37 mmol) X-Phos and 340 mg (1.5 mmol) K₃PO₄in 4 mL dioxane. The reaction mixture is stirred for 60 min at 140° C.under microwave irradiation. The solvent is removed under reducedpressure before DMF is added and the formed precipitate is filtered off.The product is isolated from the mother liquid by RP-HPLC chromatographyusing an ACN/H₂O-gadient. Yield: 300 mg (65%).

A-36)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-methyl-pyridin-4-yl]-2-chloro-benzoicacid

The title compound is synthesized according to general procedure GP4starting from 460 mg (1.2 mmol)4-[3-(6-amino-pyridin-3-ylethynyl)-2-methyl-pyridin-4-yl]-2-chloro-benzoicacid methyl ester using 2.4 mL (2.4 mmoL) 1 N NaOH in 10 mL THF. Theproduct is purified by chromatography on silica gel using anDCM/MeOH-gradient (100:0 to 90:10, NH₃). Yield: 420 mg (95%).

A-37)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid methyl ester

The title compound is synthesized according to general procedure GP3starting from 3.2 g (12.3 mmol)5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using3.6 g (18.4 mmol) 3-Fluoro-4-methoxycarbonylphenyl boronic acid, 561 mg(0.61 mmol) Pd₂(dba)₃, 877 mg (1.84 mmol) X-Phos, 519 mg (12.3 mmol)LiCl and 3.39 g (14.7 mmol) K₃PO₄ in a mixture of 60 mL1,2-dimethoxyethane and 10 mL water. The reaction mixture is stirred for16 h at 95° C. After completion of the reaction, the mixture is pouredinto water and the formed precipitate is collected by filtration. Theproduct is purified by chromatography on silica gel using anDCM/MeOH-mixture (3% MeOH, flow 55 mL/min) Yield: 2.46 g (53%).

A-38)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid

The title compound is synthesized according to general procedure GP4starting from 2.36 g (6.3 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid methyl ester (A-37) using 9.4 mL (9.4 mmoL) 1N NaOH in 40 mL THF.The reaction mixture is stirred for 2 h at 95° C. The solvent is removedunder reduced pressure, the crude product is taken up with water and thepH is adjusted to 5 (with 1N HCl). The precipitate is collected byfiltration. Yield after drying: 2.2 g (97%).

A-39)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-benzoicacid methyl ester

The title compound is synthesized according to general procedure GP3starting from 2.0 g (7.8 mmol)5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using2.5 g (11.6 mmol) 3-chloro-4-methoxycarbonylphenyl boronic acid, 335 mg(0.39 mmol) Pd₂(dba)₃, 555 mg (1.2 mmol) X-Phos and 2.7 g (11.6 mmol)K₃PO₄ in a mixture of 100 mL DME and 20 mL water. The reaction mixtureis stiffed under reflux for 4 days. The DME is removed under reducedpressure and the aqueous is extracted with ethyl acetate. The organicphase is dried over Na₂SO₄, filtered and the solvent removed undervacuum. The product is purified by chromatography on silica gel using anDCM/MeOH-gradient. Yield: 0.59 g (19%).

A-40)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-benzoicacid

The title compound is synthesized according to general procedure GP4starting from 1.1 g (2.8 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-benzoicacid methyl ester (A-39) using 134 mg (5.6 mmoL) LiOH in a mixture of100 mL THF and 20 mL water. After completion of the reaction, THF isremoved under reduced pressure, the aqueous solution is acidified with1N HCl to pH ˜1 before the pH is adjusted to 6 with saturated aqueousNaHCO₃ solution. The precipitated product is collected by filtration,washed with water and methanol. Yield: 760 mg (72%).

A-41)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-methoxy-benzoicacid methyl ester

The title compound is synthesized according to general procedure GP3starting from 1.5 g (5.0 mmol)5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using1.6 g (7.4 mmol) 3-methoxy-4-methoxycarbonylphenyl boronic acid, 135 mg(0.15 mmol) Pd₂(dba)₃, 354 mg (0.74 mmol) X-Phos and 2.2 g (9.4 mmol)K₃PO₄ in 20 mL dioxane. The reaction mixture is stirred under refluxover night. The solvent is removed under reduced pressure before wateris added and the formed precipitate is collected by filtration. Theproduct is purified by chromatography on silica gel using aDCM/MeOH-gradient.

Yield: 1.07 g (56%).

A-42)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-methoxy-benzoicacid

The title compound is synthesized according to general procedure GP4starting from 1.07 g (2.77 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-methoxy-benzoicacid methyl ester (A-41) using 2.4 mL (2.4 mmoL) 1N NaOH in 30 mL THF.The reaction mixture is stirred over night, after complete consumptionof the starting material the pH is adjusted to 4 (using 1N HCl). As noprecipitate is formed, the aqueous phase is extracted with DCM. However,the product precipitates upon addition of DCM and is collected byfiltration. Additional product is precipitated from the mother liquid byadjustment of the pH to 6 (using 1N NaOH). Yield of the combinedfractions: 990 mg (96%).

A-43)4-[3-(6-Amino-2-ethyl-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid methyl ester

The title compound is synthesized according to general procedure GP3starting from 1.29 g (4.5 mmol)5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-6-ethyl-pyridin-2-ylamine(A-30) using 1.34 mg (6.8 mmol) 3-Fluoro-4-methoxycarbonylphenyl boronicacid, 1.4 g (0.9 mmol) Pd(PPh₃)₄ and 1.19 g (8.6 mmol) K₂CO₃ in amixture of 9 mL 1,2-dimethoxyethane and 2.25 mL water. The reactionmixture is stirred twice for 30 min at 130° C. under microwaveirradiation. The product is precipitated by the addition of water,filtered off and purified by chromatography on silica gel using acyclohexane/ethyl acetate gradient.

Yield: 944 mg (52%).

A-44)4-[3-(6-Amino-2-ethyl-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid

The title compound is synthesized according to general procedure GP4starting from 944 mg (2.34 mmol)4-[3-(6-Amino-2-ethyl-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid methyl ester (A-43) using 3.5 mL (3.5 mmoL) 1N NaOH in 25 mL THF.The reaction mixture is diluted with water and the product extractedwith DCM. The organic phase is separated and the solvent removed underreduced pressure. The crude product is used without furtherpurification. Yield: 945 mg (>100%).

A-45)4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-benzoicacid methyl ester

The title compound is synthesized according to general procedure GP3starting from 770 mg (2.8 mmol)5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-yl]-methyl-amine(A-30) using 841 mg (4.3 mmol) 3-Fluoro-4-methoxycarbonylphenyl boronicacid, 882 mg (0.57 mmol) Pd(PPh₃)₄ and 752 mg (5.4 mmol) K₂CO₃ in amixture of 7.5 mL 1,2-dimethoxyethane and 1.5 mL water. The reactionmixture is stirred for 30 min at 180° C. under microwave irradiation.The reaction mixture is filtered off and the product is precipitatedfrom the solution by addition of water. After filtration, the product ispurified by chromatography on silica gel using an DCM/MeOH-gradient.Yield: 850 mg (77%).

A-46)4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-benzoicacid

The title compound is synthesized according to general procedure GP4starting from 850 mg (2.18 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid methyl ester (A-45) using 3.3 mL (3.3 mmoL) 1N NaOH in 22 mL THF.The reaction mixture is stirred for 72 h at 65° C. The product isprecipitated by addition of water and is collected by filtration. Yieldafter drying: 747 mg (91%).

Examples 1-130

The example compounds are synthesized according to the generalprocedures GP3 (Suzuki coupling) or GP5-9 (formation of amides or ureas)as outlined above. The appropriate starting materials required forsynthesis can be deduced from the table of the examples. All buildingblocks and reagents are either commercially available or can besynthesized by methods well known in literature.

TABLE 1 Examples Starting No. Structures material MW [M + H]⁺ t_(Ret)  1

A-36 472.0 M + H = 472/474 M − H = 470/472 tR = 1.75 (1.90)  2

A-32 455.5 M + H = 456 tR = 1.73  3

A-29 377.5 M + H = 378 (258) tR = 1.58 (1.65)  4

A-32 429.5 M + H = 429 tR = 1.51  5

A-28 300.4 M + H = 301 tR = 1.43  6

A-32 483.6 M + H = 484 tR = 1.80  7

A-36 416.9 M + H = 417/419 tR = 1.65  8

A-36 446.0 M + H = 446 tR = 1.54  9

A-36 500.0 M + H = 500 tR = 1.85 10

A-36 432.9 M + H = 433 tR = 1.54 11

A-36 390.9 M + H = 391/393 tR = 1.56 12

A-30 377.5 M + H = 378 tR = 1.54 13

A-34 437.5 M + H = 438 tR = 1.62 14

A-34 356.4 M + H = 357 tR = 1.43 15

A-34 398.5 M + H = 399 tR = 1.42 16

A-34 411.5 M + H = 412 tR = 1.43 17

A-30 314.4 M + H = 315 tR = 1.51 18

A-30 390.9 M + H = 391 tR = 1.52

Example 192-{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-phenyl}-2-methyl-propionitrile

The title compound is synthesized according to general procedure GP3starting from 100 mg (0.39 mmol)5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using110 mg (0.58 mmoL) 4-2(2-cyanopropan-2-yl)benzeneboronic acid 22 mg(0.02 mmol) Pd(PPh₃)₄ and 103 mg (0.74 mmol) K₂CO₃ in a mixture of 1.0mL DME and 0.2 mL water. The reaction mixture is stirred twice undermicrowave irradiation at 130° C. for 30 min. After completion of thereaction, water is added and the precipitate is collected by filtration.The crude product is purified by chromatography on silica gel using aDCM/MeOH-gradient. Since the product was not obtained in sufficientpurity, it was re-purified by RP-HPLC using a H₂O/ACN-gradient. Yield:30 mg (21%).

MW=366.5; [M+H]⁺=367; t_(Ret)=1.83 min

Example 205-(2,2′-Diethyl-[4,4′]bipyridinyl-3-ylethynyl)-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP3starting from 100 mg (0.39 mmol)5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using146 mg (˜60% purity, 0.58 mmoL) 2-ethyl-pyrid-4-yl boronic acid, 18 mg(0.02 mmol) Pd₂(dba)₃, 28 mg (0.06 mmol) XPhos and 107 mg (0.47 mmol)K₃PO₄ in a mixture of 6.0 mL DME. The reaction mixture is stirred twiceunder microwave irradiation at 190° C. for 300 min. The reaction mixtureis concentrated in vaccuo and the crude product is purified bychromatography on silica gel using a DCM/MeOH-gradient. Yield: 9 mg(7%).

MW=328.4; [M+H]⁺=329; t_(Ret)=1.61 min

Example 215-(2-Ethyl-2′,6′-dimethyl-[4,4′]bipyridinyl-3-ylethynyl)-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP3starting from 100 mg (0.39 mmol)5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using88 mg (0.58 mmoL) 2,6-dimethyl-pyrid-4-yl boronic acid, 18 mg (0.02mmol) Pd₂(dba)₃, 28 mg (0.06 mmol) XPhos and 107 mg (0.47 mmol) K₃PO₄ ina mixture of 6.0 mL DME. The reaction mixture is stirred twice undermicrowave irradiation at 190° C. for 300 min. The reaction mixture isconcentrated in vaccuo and the crude product is purified bychromatography on silica gel using a DCM/MeOH-gradient. Yield: 17 mg(14%).

MW=328.4; [M+H]⁺=329; t_(Ret)=1.61 min

Example 225-(6-Cyclopropyl-2′-ethyl-[3,4′]bipyridinyl-3′-ylethynyl)-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP3starting from 150 mg (0.58 mmol)5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using142 mg (0.87 mmoL) 2-cyclopropyl-pyrid-5-yl boronic acid, 4.5 mg (0.03mmol) Pd(PPh₃)₄ and 154 mg (1.11 mmol) K₂CO₃ in a mixture of 6.0 mL DMEand 1.5 mL water. The reaction mixture is stirred twice under microwaveirradiation at 150° C. for 120 min

The reaction mixture is concentrated in vaccuo and the crude product ispurified by chromatography on silica gel using a DCM/MeOH-gradient.Yield: 68 mg (34%).

MW=340.4; [M+H]⁺=341; t_(Ret)=1.51 min

Example 235-(2′-Ethyl-6-trifluoromethyl-[3,4′]bipyridinyl-3′-ylethynyl)-pyridin-2-ylamine

The title compound is synthesized according to general procedure GP3starting from 150 mg (0.58 mmol)5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using167 mg (0.87 mmoL) 2-trifluoromethyl-pyrid-5-yl boronic acid, 4.5 mg(0.03 mmol) Pd(PPh₃)₄ and 154 mg (1.11 mmol) K₂CO₃ in a mixture of 6.0mL DME and 1.5 mL water. The reaction mixture is stirred twice undermicrowave irradiation at 150° C. for 120 min. The reaction mixture isconcentrated in vaccuo and the crude product is purified bychromatography on silica gel using a DCM/MeOH-gradient. Yield: 15 mg(7%).

MW=368.4; [M+H]⁺=369; t_(Ret)=1.56 min

Example 24{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-morpholin-4-yl-methanone

The title compound is synthesized according to general procedure GP5starting from 120 mg (0.33 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid (A-38) using 43 mg (0.50 mmoL) morpholine, 139 mg (0.37 mmol) HATUand 96 μL DIEA in 1.2 mL DMF. After completion of the reaction, DMF isremoved under reduced pressure and the product is purified bychromatography on silica gel using a DCM/MeOH-gradient. Yield: 66 mg(46%).

MW=430.5; [M+H]⁺=431; t_(Ret)=1.60 min

Example 25{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-piperazin-1-yl-methanone

The title compound is synthesized according to general procedure GP5starting from 100 mg (0.28 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid (A-38) using 29 mg (0.33 mmoL) piperazine, 116 mg (0.30 mmol) HATUand 81 μL DIPEA in 1 mL DMF. After completion of the reaction, thereaction mixture is filtered and the product is isolated from theobtained solution by RP-HPLC using a H₂O/MeOH-gradient. Yield: 8 mg(6%).

MW=429.5; [M+H]⁺=430; t_(Ret)=1.29 min

Example 26{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-(4-methyl-piperazin-1-yl)-methanone

The title compound is synthesized according to general procedure GP5starting from 120 mg (0.33 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid (A-38) using 55 μL (0.50 mmoL) N-methyl piperazine, 139 mg (0.37mmol) HATU and 96 μL DIPEA in 1.2 mL DMF. After completion of thereaction, the reaction mixture is filtered and the product is isolatedfrom the obtained solution by RP-HPLC using a H₂O/MeOH-gradient. Yield:55 mg (37%).

MW=443.5; [M+H]⁺=444; t_(Ret)=1.68 min

Example 27{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-phenyl}-(4-methyl-piperazin-1-yl)-methanone

The title compound is synthesized according to general procedure GP5starting from 100 mg (0.27 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-benzoicacid (A-40) using 40 mg (0.40 mmoL) N-methyl piperazine, 102 mg (0.53mmol) EDC, 72 mg (0.53 mmol) HOBt and 68 mg (0.53 mmol) DIPEA in 1.2 mLDMF. After completion of the reaction, the reaction mixture is filteredand the product is isolated from the obtained solution by RP-HPLC usinga H₂O/ACN-gradient. Yield: 66 mg (54%).

MW=460.0; [M+H]⁺=460/62; t_(Ret)=1.64 min

Example 28{4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-phenyl}-(4-methyl-piperazin-1-yl)-methanone

The title compound is synthesized according to general procedure GP5starting from 100 mg (0.27 mmol)4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-benzoicacid (A-46) using 50 μL (0.45 mmoL) N-methyl piperazine, 101 mg (0.27mmol) HATU and 50 μL (0.29 mmol) DIPEA in 1.5 mL DMF. After completionof the reaction, the reaction mixture is filtered and the product isisolated from the obtained solution by RP-HPLC using a H₂O/ACN-gradient.Yield: 70 mg (58%).

MW=457.6; [M+H]⁺=458; t_(Ret)=1.70 min

Example 29{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-methoxy-phenyl}-(4-methyl-piperazin-1-yl)-methanone

The title compound is synthesized according to general procedure GP5starting from 70 mg (0.19 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-methoxy-benzoic acid (A-42) using 42 μL (0.38 mmoL) N-methylpiperazine, 71 mg (0.19 mmol) HATU and 35 μL (0.21 mmol) DIPEA in 1.0 mLDMF. After completion of the reaction, the reaction mixture is filteredand the product is isolated from the obtained solution by RP-HPLC usinga H₂O/ACN-gradient. Yield: 81 mg (95%).

MW=455.6; [M+H]⁺=456; t_(Ret)=1.57 min

Example 30{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-(4-ethyl-piperazin-1-yl)-methanone

The title compound is synthesized according to general procedure GP5starting from 100 mg (0.28 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid (A-38) using 38 mg (0.33 mmoL) N-ethyl piperazine, 116 mg (0.30mmol) HATU and 81 μL DIPEA in 1 mL DMF. After completion of thereaction, the reaction mixture is filtered and the product is isolatedfrom the obtained solution by RP-HPLC using a H₂O/MeOH-gradient. Yield:36 mg (28%).

MW=457.6; [M+H]⁺=458; t_(Ret)=1.66 min

Example 31{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-phenyl}-(4-ethyl-piperazin-1-yl)-methanone

The title compound is synthesized according to general procedure GP5starting from 100 mg (0.27 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-benzoicacid (A-40) using 40 mg (0.40 mmoL) N-ethyl piperazine, 102 mg (0.53mmol) EDC, 72 mg (0.53 mmol) HOBt and 68 mg (0.53 mmol) DIPEA in 1.2 mLDMF. After completion of the reaction, the reaction mixture is filteredand the product is isolated from the obtained solution by RP-HPLC usinga H₂O/ACN-gradient. Yield: 67 mg (53%).

MW=474.0; [M+H]^(E)=474/476; t_(Ret)=1.73 min

Example 32{4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-phenyl}-(4-ethyl-piperazin-1-yl)-methanone

The title compound is synthesized according to general procedure GP5starting from 100 mg (0.28 mmol)4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-benzoicacid (A-46) using 55 μL (0.33 mmoL) N-ethyl piperazine, 101 mg (0.27mmol) HATU and 50 μL DIPEA in 1.5 mL DMF. After completion of thereaction, the reaction mixture is filtered and the product is isolatedfrom the obtained solution by RP-HPLC using a H₂O/ACN-gradient. Yield:82 mg (65%).

MW=471.6; [M+H]⁺=472; t_(Ret)=1.79 min

Example 33{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-methoxy-phenyl}-(4-ethyl-piperazin-1-yl)-methanone

The title compound is synthesized according to general procedure GP5starting from 70 mg (0.19 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-methoxy-benzoicacid (A-42) using 42 mg (0.38 mmoL) N-ethyl piperazine, 71 mg (0.19mmol) HATU and 35 μL (0.21 mmol) DIPEA in 1.0 mL DMF. After completionof the reaction, the reaction mixture is filtered and the product isisolated from the obtained solution by RP-HPLC using a H₂O/ACN-gradient.Yield: 85 mg (97%).

MW=469.6; [M+H]⁺=470; t_(Ret)=1.64 min

Example 34{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-(4-cyclopropyl-piperazin-1-yl)-methanone

The title compound is synthesized according to general procedure GP5starting from 120 mg (0.33 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid (A-38) using 63 mg (0.50 mmoL) N-cyclopropyl piperazine, 139 mg(0.37 mmol) HATU and 96 μL DIPEA in 1.2 mL DMF. After completion of thereaction, the reaction mixture is filtered and the product is isolatedfrom the obtained solution by RP-HPLC using a H₂O/ACN-gradient. Yield:30 mg (20%).

MW=469.6; [M+H]⁺=470; t_(Ret)=1.82 min

Example 35{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-methanone

The title compound is synthesized according to general procedure GP5starting from 320 mg (0.89 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid (A-38) using 181 mg (1.06 mmoL) 1-tetrahydro-pyran-4-yl piperazine,370 mg (0.97 mmol) HATU and 258 μL DIPEA in 3 mL DMF. After completionof the reaction, the reaction mixture is filtered and the product isisolated from the obtained solution by RP-HPLC using aH₂O/MeOH-gradient. Yield: 90 mg (20%).

MW=513.6; [M+H]⁺=514; t_(Ret)=1.62 min

Example 36{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-phenyl}-(4-morpholin-4-yl-piperidin-1-yl)-methanone

The title compound is synthesized according to general procedure GP5starting from 100 mg (0.27 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-benzoicacid (A-40) using 68 mg (0.40 mmoL) 4-piperidin-4-yl morpholine, 102 mg(0.53 mmol) EDC, 72 mg (0.53 mmol) HOBt and 68 mg (0.53 mmol) DIPEA in1.2 mL DMF. After completion of the reaction, the reaction mixture isfiltered and the product is isolated from the obtained solution byRP-HPLC using a H₂O/ACN-gradient. Yield: 73 mg (51%).

MW=530.1; [M+H]⁺=530/532; t_(Ret)=1.66 min

Example 37{4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-phenyl}-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-methanone

The title compound is synthesized according to general procedure GP5starting from 100 mg (0.27 mmol)4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-benzoicacid (A-46) using 68 mg (0.40 mmoL) tetrahydro-pyran-4-yl piperazine,101 mg (0.27 mmol) HATU and 50 μL DIPEA in 1.5 mL DMF. After completionof the reaction, the reaction mixture is filtered and the product isisolated from the obtained solution by RP-HPLC using a H₂O/ACN-gradient.Yield: 59 mg (42%).

MW=527.6; [M+H]⁺=528; t_(Ret)=1.81 min

Example 381-(4-{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoyl}-piperazin-1-yl)-ethanone

The title compound is synthesized according to general procedure GP5starting from 100 mg (0.28 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid (A-38) using 46 mg (0.36 mmoL) N-acetyl piperazine, 116 mg (0.30mmol) HATU and 81 μL DIPEA in 1 mL DMF. After completion of thereaction, the reaction mixture is filtered and the product is isolatedfrom the obtained solution by RP-HPLC using a H₂O/ACN-gradient. Yield:69 mg (53%).

MW=471.5; [M+H]⁺=472; t_(Ret)=1.52 min

Example 394-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-N-(2-methoxy-ethyl)-N-methyl-benzamide

The title compound is synthesized according to general procedure GP5starting from 320 mg (0.89 mmol)4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoicacid (A-38) using 95 mg (1.06 mmoL) 2-methoxy methylamine, 370 mg (0.97mmol) HATU and 258 μL DIPEA in 3 mL DMF. After completion of thereaction, the reaction mixture is filtered and the product is isolatedfrom the obtained solution by RP-HPLC using a H₂O/ACN-gradient. Yield:130 mg (34%).

MW=432.5; [M+H]⁺=433; t_(Ret)=1.62 min

TABLE 1 Examples (cont.) Starting No. Structures material MW [M + H]⁺t_(Ret)  40

355.4 M + H = 356 tR = 1.62  41

375.9 M + H = 376 tR = 1.61  42

A-28 432.9  43

A-28 374.4  44

A-28 376.8  45

434.9  46

A-28 390.9  47

A-28 275.3 M + H = 276 tR = 1.19  48

A-38 497.6 M + H = 498 tR = 1.89  49

462.0  50

418.5  51

431.5  52

416.5  53

A-38 485.6 M + H = 486 tR = 1.83  54

414.5 M + H = 415 (358) tR = 1.32 (1.25)  55

415.5 M + H = 416 (358) tR = 1.35 (1.25)  56

343.4 M + H = 344 tR = 1.30  57

357.4 M + H = 358 tR = 1.25  58

A-28 289.3 M + H = 290 (497) tR = 1.23 (1.53)  59

443.5 M + H = 444 tR = 1.49  60

404.4 M + H = 405 tR = 1.30  61

418.5 M + H = 419 tR = 1.35  62

471.6 M + H = 472 tR = 1.59  63

485.6 M + H = 486 tR = 1.69  64

471.6 M + H = 472 tR = 1.56  65

471.6 M + H = 472 tR = 1.57  66

425.5 M + H = 426 tR = 1.65  67

399.5 29M + H = 400 tR = 1.29  68

387.4 M + H = 388 tR = 1.44  69

412.5 M + H = 413 tR = 1.30  70

401.5 M + H = 402 tR = 1.35  71

428.5 M + H = 429 tR = 1.39  72

397.5 M + H = 398 tR = 1.47  73

A-38 471.6 M + H = 472 tR = 1.79  74

A-38 483.6 M + H = 484 tR = 1.78  75

A-38 418.5 M + H = 419 tR = 1.58  76

A-38 444.5 M + H = 445 tR = 1.58  77

A-38 457.6 M + H = 458 tR = 1.58  78

A-38 458.5 M + H = 459 tR = 1.68  79

A-38 458.5 M + H = 459 tR = 1.56  80

A-38 444.5 M + H = 445 tR = 1.49  81

A-38 471.6 M + H = 472 tR = 1.75  82

A-38 487.6 M + H = 488 tR = 1.62  83

A-38 514.6 VB1HUJ00188 PA1 tR = 1.54  84

390.9 M + H = 391 tR = 1.45  85

377.5 M + H = 378 tR = 1.47  86

404.9 M + H = 405 tR = 1.55  87

391.5 M + H = 392 tR = 1.58  88

404.9 M + H = 405 tR = 1.56  89

317.4 M + H = 318 tR = 1.73  90

A-38 483.6 M + H = 484 tR = 1.75  91

A-38 469.6 M + H = 470 tR = 1.68  92

A-38 515.6 M + H = 516 tR = 1.74  93

A-38 485.6 M + H = 486 tR = 1.80  94

A-38 471.6 M + H = 472 tR = 1.70  95

A-38 471.6 M + H = 472 tR = 1.66  96

A-38 457.6 M + H = 458 tR = 1.62  97

A-38 455.5 M + H = 456 (389) tR = 1.50 (1.56)  98

A-38 535.6 M + H = 536 tR = 1.91  99

446.5 100

457.6 M + H = 458 tR = 1.62 101

471.6 M + H = 472 tR = 1.70 102

499.6 M + H = 500 tR = 1.86 103

501.6 M + H = 502 tR = 1.64 104

A-38 485.6 M + H = 486 tR = 1.51 105

444.5 M + H = 445 tR = 1.57 106

457.6 M + H = 458 tR = 1.57 107

A-28 354.3 M + H = 355 tR = 1.61 108

A-28 326.4 M + H = 327 tR = 1.57 109

428.5 M + H = 429 tR = 1.70 110

483.6 M + H = 484 tR = 1.77 111

443.5 M + H = 444 tR = 1.50 112

513.6 M + H = 514 tR = 1.63 113

487.6 M + H = 488 tR = 1.56 114

485.6 M + H = 486 tR = 1.77 115

457.6 M + H = 458 tR = 1.60 116

A-46 499.6 M + H = 500 tR = 1.97 117

A-46 497.6 M + H = 498 tR = 1.92 118

A-46 485.6 M + H = 486 tR = 1.90 119

A-46 501.6 M + H = 502 tR = 1.75 120

A-44 442.5 M + H = 443 tR = 1.79 121

A-44 458.5 M + H = 459 tR = 1.69 122

A-44 497.6 M + H = 498 tR = 1.88 123

342.4 M + H = 343 tR = 1.81 124

342.4 M + H = 343 tR = 1.70 125

446.5 M + H = 447 tR = 1.60 126

A-42 483.6 M + H = 484 tR = 1.79 127

A-42 495.6 M + H = 469 tR = 1.82 128

A-38 356.5 M + H = 357 tR = 1.89 129

A-42 483.6 M + H = 484 tR = 1.77 130

A-42 455.5 M + H = 456 tR = 1.42

Analytical Methods

HPLC: Agilent 1100 Series MS: Agilent LC/MSD SL column: Phenomenex,Mercury Gemini C18, 3 μm, 2.0 × 20 mm, Part. No. 00M-4439-B0-CE solventA: 5 mM NH₄HCO₃/20 mM NH₃ B: acetonitrile HPLC grade detection: MS:Positive and negative mass range: 120-700 m/z fragmentor: 70 gain EMV: 1threshold: 150 stepsize: 0.25 UV: 315 nm bandwidth: 170 nm reference:off range: 210-400 nm range step: 2.00 nm peakwidth: <0.01 min slit: 2nm injection: 5 μL flow: 1.00 mL/min column temperature: 40° C.gradient:      0.00 min 5% B 0.00-2.50 min 5% -> 95% B 2.50-2.80 min 95%B 2.81-3.10 min 95% -> 5% B

Analytical Method 2

Instrument: Agilent 1100-SL: incl. ELSD/DAD/MSD Chromatography: Column:Phenomenex Gemini ® C18, 50 × 2.0 mm, 3μ Method “Acid” Eluent A: 0.1%formic acid in acetonitrile Eluent B: 0.1% formic acid in Water LinearGradient program: t₀ = 2% A, t_(3.5 min) = 98% A, t_(6 min) = 98% AFlow: 1 mL/min Column oven temperature: 35° C. Method “Base” Eluent A:10 mM ammonia in acetonitrile Eluent B: 10 mM ammonia in water LinearGradient program: t₀ = 2% A, t_(3.5 min) = 98% A, t_(6 min) = 98% AFlow: 1 mL/min Column oven temperature: 35° C. Evaporative LightScattering Detector (ELSD): Instrument: Polymer Laboratories PL-ELS 2100Nebuliser gas flow: 1.1 L/min N₂ Nebuliser temp: 50° C. Evaporationtemp: 80° C. Lamp: Blue LED 480 nm Diode Array Detector (DAD):Instrument: Agilent G1316A Sample wavelength: 220-320 nm Referencewavelength: Off Mass Spectroscopy (MSD): Instrument: Agilent LC/MSD-SLIonisation: ESI (Positive & Negative) Mass range: 100-800

Abbreviations Used

ACN acetonitrile Me methyl bu butyl min minute(s) CDI carbonyldiimidazole mL millilitre d day(s) MeOH methanole DC thin layerchromatography MS mass spectrometry DCM dichloromethane N normal DIPEAdiisopropylethyl amine NIS N-iodosuccinimide DME 1,2-dimethoxyethane NMPN-methylpyrrolindinone DMF N,N-dimethylformamide NMR nuclear resonancespectroscopy DMSO dimethylsulphoxide NP normal phase EDC 1-Ethyl-3-(3-ppm part per million dimethyllaminopropyl)carbodiimide (hydrochloride)Et ethyl Rf retention factor h hour(s) RP reversed phase HATUO-(7-Azabenzotriazol-1-yl)- prep preparativeN,N,N′,N′-tetramethyluronium hexafluorophosphate HOBt1-Hydroxybenzotriazole RT room temperature HPLC high performance liquidtert tertiary chromatography iPr isopropyl t_(Ret) retention time LCliquid chromatography THF tetrahydrofuran M molar TMS tetramethylsilanylXPhos 2-Dicyclohexylphosphino- 2′,4′,6′-triisopropylbiphenyl

The Examples that follow describe the biological activity of thecompounds according to the invention without restricting the inventionto these Examples.

Inhibition of Proliferation: CyQuant PC-3 Description:

The CyQuant NF assay is based on measurement of cellular DNA content viafluorescent dye binding. Because cellular DNA content is highlyregulated, it is closely proportional to cell number. The extent ofproliferation is determined by comparing cell counts for samples treatedwith drugs with untreated controls. The assay is not dependent onphysiological activities that may exhibit cell number-independentvariability.

In the assay, a DNA-binding dye in combination with a plasma membranepermeabilization reagent is used. The medium is aspirated, replaced withdye binding solution, cells are incubated for 30-60 min, thenfluorescence is measured (excitation at 485 nm, emission detection at530 nm). Data are expressed as fluorescence emission intensity units asa function of time of incubation.

Cells and Reagents:

PC-3 cells Human prostate carcinoma cells (ATCC CRL-1435) CyQuant NFInvitrogen Cat.# C35006 assay PBS (w/o Ca, Life Technologies, Gibco BRL(Cat. No. 4190-094) Mg) F-12K Medium Life Technologies, Gibco BRL (Cat.No. 21127-022) Fetal calf serum Life Technologies, Gibco BRL (Cat. No.10270-106)

Equipment:

96-well plates, flat bottom (Falcon, Cat. No.: 353072)

96-well plates, U-shaped (Costar, Cat. No.: 3799)

CO₂-Incubator

Microplate Reader, Wallac Victor

Procedure:

-   Day 0: Seed 3000 PC-3 cells (cultured in F-12K/10% FCS) in 150 μl    medium into a 96-well plate, flat bottom (include medium blank).    Incubate plates at 37° C. in a CO₂ incubator overnight.-   Day 1: Dilute compounds to a concentration 80μM→1:5 in medium, 7    dilution steps, in 96-well plates.    -   Add 50 μl per well of each dilution (total volume per well 200        μl;    -   final conc. of cpds: 20μM→1:5). If required, test further        dilutions.    -   All concentrations are tested in duplicates or triplicates.-   Controls: Cells w/o cpd. (+50 μl medium+DMSO).    -   Cells are incubated with compounds for 3 days.-   Day 4: Aspirate off medium and replace with 100 μl of 1× dye binding    solution (22 μl CyQuant NF dye reagent added to 11 ml of 1× HBSS    buffer). Cover the microplate and incubate for 30-60 min for    equilibration of dye-DNA binding. Measure the fluorescence intensity    in a microplate reader (excitation at 485 nm, emission detection at    530 nm).

Evaluation:

-   -   Calculate IC₅₀ using GraphPad Prism (Fifty)        Inhibition of mTOR-Induced p-4E-BP1 Phosphorylation (TR-FRET        mTOR Activity Kit; Invitrogen)

Materials:

-   -   GFP-4E-BP1 substrate; Invitrogen order no. PV4759    -   Lanthascreen Tb-anti-p4E-BP1 (pThr46) Antibody Kit; Invitrogen        order no. PV4758    -   FRAP1 (mTOR) kinase; Invitrogen order no. PV4753    -   ATP 10 mM    -   5× Assay Buffer (250 mM HEPES pH7.5, 0.05% Polysorbate 20, 5 mM        EGTA, 50 mM MnCl2)    -   EDTA 500 mM

Determining IC50 Values for Test Compounds: Kinase Reaction Conditions:

400 nM GFP-4E-BP1, 8 μM ATP, ˜150 ng/mL mTOR, 50 mM HEPES

pH 7.5, 0.01% Polysorbate 20, 1 mM EGTA, 10 mM MnCl2, and variableamounts of test compounds.

Preparation of Reagents:

Note: Thaw and keep mTOR, the substrate, ATP, and the antibody on iceprior to making working dilutions. Working dilutions of these componentscan be kept at room temperature for short periods of time the day ofuse.

1. Add 2 ml of 5× Assay Buffer to 8 ml water to prepare 10 ml of 1×Assay Buffer.

Note: The concentration of 1× Assay Buffer is 50 mM HEPES pH 7.5, 0.01%Polysorbate 20, 1 mM EGTA, and 10 mM MnCl₂.

2. Prepare Antibody/EDTA Solution by first adding 2.75 μl of Tb-antip4E-BP1 Antibody to 2397 μl of LanthaScreen™ TR-FRET Dilution Buffer.Then, add 100 μl of 0.5 M EDTA.

3. Prepare 4× Substrate/Enzyme Solution by first adding 72 μl ofGFP-4E-BP1 (22 μM) to 926 μl of 1× Assay Buffer. Then, add 1.6 μl ofmTOR (0.45 mg/mL).

4. Prepare ATP Solution by adding 3.2 μl of 10 mM ATP to 1997 μl of 1×Assay Buffer.

Serial Dilution of Inhibitors (16 point curve):

Note: It is recommended that inhibitors be serially diluted in DMSO,then diluted to a 4× working concentration with 1× Assay Buffer. Thebelow procedure describes dilution of compounds in a 96-well formatprior to transfer to a 384-well format for kinase assays. This procedurecalls for dilution of the compounds in 2 adjacent columns of a 96-wellplate, which upon transfer to a single column of a 384-well plate withan 8-channel pipette will align the samples in order of concentration.

1. Dispense 40 μl of DMSO to two adjacent columns of a 96 well plate percompound (e.g. columns 1 and 2).

2. Add 10 μl of inhibitor stock (10 mM) to the first well of the firstcolumn (A1) and mix.

3. Remove 10 μl from A1 and transfer to the adjacent well in the nextcolumn (B1) and mix.

4. Remove 10 μl from B1 and transfer to the next well in the firstcolumn (B2) and mix.

5. Repeat this dilution pattern through well H1 and leave the last well(H2) as DMSO only.

6. Remove 4 μl of diluted compounds and add to 96 μl of 1× Assay Bufferin a 96-well plate making 4× compound dilutions.

Kinase Reaction:

1. Add 2.5 μl of 4× compound dilutions from the first column of the96-well plate to every other well of column 1 of a 384-well plate withan 8-channel pipette. Repeat for columns 2 and 3.

2. Add 2.5 μl of 4× compound dilutions from the second column of the96-well plate to the empty wells of column 1 of the 384-well plate withan 8-channel pipette. Repeat for columns 2 and 3.

Note: This procedure aligns the compound dilutions in order ofconcentration.

3. Add 2.5 μl of 4× Enzyme/Substrate Solution to all columns 1-6.

4. Preincubate for 30 min. at RT (shaker).

5. Add 5 μl of ATP Solution to all wells to start reactions.

6. Shake the assay plate on a plate shaker for 30 seconds.

7. Incubate the assay plate for one hour at room temperature (20-25°C.).

Stop Step and Fluorescence Detection:

1. Add 10 μl of Antibody/EDTA Solution to each well in columns 1-9.

2. Shake the assay plate on a plate shaker for 30 seconds.

3. Incubate the assay plate for one hour at room temperature (20-25°C.).

4. Measure the GFP (FRET) and terbium (reference) emission signals on afluorescence plate reader (e.g. Perkin Elmer Envision).

Data Analysis:

1. Calculate the emission ratio for each sample by dividing the GFP(FRET) signal by the terbium (reference) signal.

2. Plot the concentration of each compound versus the emission ratio.Determine the concentration of compound required to reach 50% of themaximum signal (IC50). Determination of IC50 values can be obtained bycurve fitting (sigmoidal dose response, variable slope) using Prismsoftware from GraphPad).

TABLE 2 Biological data Example mTOR (IC50) CQ PC3 (EC50) 1 0.66 45 2 244 3 7 288 4 7 100 5 236 6 5 80 7 4 78 8 2 44 9 4 49 10 3 75 11 1 56 1217 57 13 8 121 14 3 65 15 7 122 16 7 160 17 10 97 18 5 42 19 93 20 9 24821 78 22 47 344 23 26 214 24 3 74 25 4 85 26 2 25 27 28 11 178 29 6 16130 2 40 31 32 9 310 33 32 236 34 4 71 35 1 30 36 37 5 160 38 2 39 3 5840 207 1953 41 497 2113 42 4 236 43 12 355 44 42 514 45 6 224 46 5 18847 97 644 48 4 31 49 19 394 50 6 119 51 20 326 52 26 617 53 5 104 54 35306 55 10 200 56 28 354 57 9 106 58 95 519 59 37 426 60 3 103 61 3 27562 19 309 63 23 451 64 33 470 65 69 385 66 60 425 67 17 156 68 88 429 6928 206 70 20 130 71 105 343 72 21 186 73 2 131 74 2 69 75 7 110 76 2 3577 10 100 78 3 81 79 2 55 80 2 114 81 2 54 82 2 40 83 2 75 84 85 688 855 136 86 77 694 87 5 45 88 4 86 89 113 537 90 4 79 91 3 35 92 9 109 9310 70 94 9 134 95 9 58 96 6 59 97 9 121 98 42 185 99 28 548 100 5 45 10138 176 102 69 66 103 21 85 104 4 12 105 44 121 106 17 88 107 27 196 10837 237 109 21 152 110 11 100 111 3 50 112 4 77 113 5 114 114 5 84 115 19368 116 10 324 117 14 566 118 13 247 119 13 255 120 79 149 121 41 166122 96 126 123 44 616 124 15 84 125 24 425 126 33 256 127 27 252 128 56315 129 11 237 130 3 262

The substances of the present invention are PI3 kinase pathwayinhibitors, in particular of the serine/threonine kinase mTOR and/ormembers of the lipid kinase family Pi3K. On account of their biologicalproperties, the novel compounds of the general formula (1) and theirisomers and their physiologically tolerated salts are suitable fortreating diseases which are characterized by excessive or anomalous cellproliferation. These diseases include, for example: viral infections(e.g. HIV and Kaposi's sarcoma); inflammation and autoimmune diseases(e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis andwound healing); bacterial, fungal and/or parasitic infections;leukaemias, lymphomas and solid tumours; skin diseases (e.g. psoriasis);bone diseases; cardiovascular diseases (e.g. restenosis andhypertrophy). In addition, the compounds are useful for protectingproliferating cells (e.g. hair cells, intestinal cells, blood cells andprogenitor cells) from DNA damage due to irradiation, UV treatmentand/or cytostatic treatment (Davis et al., 2001).

For example, the following cancer diseases can be treated with compoundsaccording to the invention, without, however, being restricted thereto:brain tumours, such as acoustic neurinoma, astrocytomas such as piloidastrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma,gemistocytic astrocytoma, anaplastic astrocytoma and glioblastomas,brain lymphomas, brain metastases, hypophyseal tumour such asprolactinoma, HGH (human growth hormone) producing tumour andACTH-producing tumour (adrenocorticotrophic hormone),craniopharyngiomas, medulloblastomas, meningiomas andoligodendrogliomas; nerve tumours (neoplasms) such as tumours of thevegetative nervous system such as neuroblastoma sympathicum,ganglioneuroma, paraganglioma (phaeochromocytoma and chromaffinoma) andglomus caroticum tumour, tumours in the peripheral nervous system suchas amputation neuroma, neurofibroma, neurinoma (neurilemoma, schwannoma)and malignant schwannoma, as well as tumours in the central nervoussystem such as brain and spinal cord tumours; intestinal cancer such asrectal carcinoma, colon carcinoma, anal to carcinoma, small intestinetumours and duodenal tumours; eyelid tumours such as basalioma or basalcell carcinoma; pancreatic gland cancer or pancreatic carcinoma; bladdercancer or bladder carcinoma; lung cancer (bronchial carcinoma) such assmall-cell bronchial carcinomas (oat cell carcinomas) and non-small-cellbronchial carcinomas such as squamous epithelium carcinomas,adenocarcinomas and large-cell bronchial carcinomas; breast cancer suchas mammary carcinoma, such as infiltrating ductal carcinoma, colloidcarcinoma, lobular invasive carcinoma, tubular carcinoma, adenoid cysticcarcinoma, and papillary carcinoma; non-Hodgkin's lymphomas (NHL) suchas Burkitt's lymphoma, low-malignancy non-Hodkgin's lymphomas (NHL) andmucosis fungoides; uterine cancer or endometrial carcinoma or corpuscarcinoma; CUP syndrome (cancer of unknown primary); ovarian cancer orovarian carcinoma such as mucinous, endometrial or serous cancer; gallbladder cancer; bile duct cancer such as Klatskin's tumour; testicularcancer such as seminomas and non-seminomas; lymphoma (lymphosarcoma)such as malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas(NHL) such as chronic lymphatic leukaemia, hair cell leukaemia,immunocytoma, plasmocytoma (multiple myeloma), immunoblastoma, Burkitt'slymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastomaand lymphoblastoma; laryngeal cancer such as vocal cord tumours,supraglottal, glottal and subglottal laryngeal tumours; bone cancer suchas osteochondroma, chondroma, chrondoblastoma, chondromyxoidfibroma,osteoma, osteoid-osteoma, osteoblastoma, eosinophilic granuloma, giantcell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma,reticulosarcoma, plasmocytoma, fibrous dysplasia, juvenile bone cyst andaneurysmatic bone cyst; head/neck tumours such as tumours of the lips,tongue, floor of the mouth, oral cavity, gingiva, pallet, salivaryglands, pharynx, nasal cavities, paranasal sinuses, larynx and middleear; liver cancer such as liver cell carcinoma or hepatocellularcarcinoma (HCC); leukaemias, such as acute leukaemias, such as acutelymphatic/lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML);chronic leukaemias such as chronic lymphatic leukaemia (CLL), chronicmyeloid leukaemia (CML); stomach cancer or stomach carcinoma such aspapillary, tubular and mucinous adenocarcinoma, signet ring cellcarcinoma, adenoid squamous cell carcinoma, small-cell carcinoma andundifferentiated carcinoma; melanomas such as superficially spreading,nodular malignant lentigo and acral lentiginous melanoma; renal cancer,such as kidney cell carcinoma or hypernephroma or Grawitz's tumour;oesophageal cancer or oesophageal carcinoma; cancer of the penis;prostate cancer; pharyngeal cancer or pharyngeal carcinomas such asnasopharyngeal carcinomas, oropharyngeal carcinomas and hypopharyngealcarcinomas; retinoblastoma; vaginal cancer or vaginal carcinoma;squamous epithelium carcinomas, adeno carcinomas, in situ carcinomas,malignant melanomas and sarcomas; thyroid gland carcinomas such aspapillary, follicular and medullary thyroid gland carcinoma, and alsoanaplastic carcinomas; spinalioma, prickle cell carcinoma and squamousepithelium carcinoma of the skin; thymomas, urethral cancer and vulvarcancer.

The novel compounds can be used for the prevention or short-term orlong-term treatment of the abovementioned diseases including, whereappropriate, in combination with other state-of-the-art compounds suchas other anti-tumour substances, cytotoxic substances, cellproliferation inhibitors, antiangiogenic substances, steroids orantibodies.

The compounds of the general formula (1) can be used on their own or incombination with other active compounds according to the invention and,where appropriate, in combination with other pharmacologically activecompounds as well. Chemotherapeutic agents which can be administered incombination with the compounds according to the invention include,without being restricted thereto, hormones, hormone analogs andantihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant,megestrol acetate, flutamide, nilutamide, bicalutamide,aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate,fludrocortisone, fluoxymesterone, medroxyprogesterone and octreotide),aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole,exemestane and atamestane), LHRH agonists and antagonists (e.g.goserelin acetate and luprolide), inhibitors of growth factors (growthfactors such as platelet-derived growth factor and hepatocyte growthfactor, examples of inhibitors are growth factor antibodies, growthfactor receptor antibodies and tyrosine kinase inhibitors, such asgefitinib, imatinib, lapatinib, Erbitux® and trastuzumab);antimetabolites (e.g. antifolates such as methotrexate and raltitrexed,pyrimidine analogs such as 5-fluorouracil, capecitabine and gemcitabine,purine and adenosine analogs such as mercaptopurine, thioguanine,cladribine and pentostatin, cytarabine and fludarabine); antitumourantibiotics (e.g. anthracyclines, such as doxorubicin, daunorubicin,epirubicin and idarubicin, mitomycin C, bleomycin, dactinomycin,plicamycin and streptozocin); platinum derivatives (e.g. cisplatin,oxaliplatin and carboplatin); alkylating agents (e.g. estramustine,meclorethamine, melphalan, chlorambucil, busulphan, dacarbazine,cyclophosphamide, ifosfamide and temozolomide, nitrosoureas such ascarmustine and lomustine and thiotepa); antimitotic agents (e.g. vincaalkaloids such as vinblastine, vindesine, vinorelbine and vincristine;and taxans such as paclitaxel and docetaxel); topoisomerase inhibitors(e.g. epipodophyllotoxins such as etoposide and etopophos, teniposide,amsacrine, topotecan, irinotecan and mitoxantrone) and variouschemotherapeutic agents such as amifostin, anagrelide, clodronate,filgrastin, interferon alpha, leucovorin, rituximab, procarbazine,levamisole, mesna, mitotan, pamidronate and porfimer.

Examples of suitable forms for use are tablets, capsules, suppositories,solutions, in particular solutions for injection (s.c., i.v., i.m.) andinfusion, syrups, emulsions or dispersible powders. In this connection,the proportion of the pharmaceutically active compound(s) should in eachcase be in the range of 0.1-90% by weight, preferably 0.5-50% by weight,of the total composition, that is in quantities which are sufficient toachieve the dosage range which is specified below. If necessary, thedoses mentioned can be given several times a day.

Appropriate tablets can be obtained, for example, by mixing the activecompound(s) with known auxiliary substances, for example inert diluents,such as calcium carbonate, calcium phosphate or lactose, disintegrants,such as maize starch or alginic acid, binders, such as starch orgelatine, lubricants, such as magnesium stearate or talc, and/or agentsfor achieving a depot effect, such as carboxymethyl cellulose, celluloseacetate phthalate or polyvinyl acetate. The tablets can also compriseseveral layers.

Correspondingly, sugar-coated tablets can be produced by coating cores,which have been prepared in analogy with tablets, with agents which arecustomarily used in sugar coatings, for example collidone or shellac,gum arabic, talc, titanium dioxide or sugar. The core can also compriseseveral layers in order to achieve a depot effect or to avoidincompatibilities. In the same way, the sugar coating can also compriseseveral layers in order to achieve a depot effect, with it beingpossible to use the auxiliary substances which are mentioned above inthe case of the tablets.

Syrups of the active compounds or active compound combinations accordingto the invention can additionally comprise a sweetening agent, such assaccharine, cyclamate, glycerol or sugar as well as a taste-improvingagent, e.g. flavouring agents such as vanillin or orange extract. Theycan also comprise suspension aids or thickeners, such as sodiumcarboxymethyl cellulose, wetting agents, for example condensationproducts of fatty alcohols and ethylene oxide, or protectants such asp-hydroxybenzoates.

Injection and infusion solutions are produced in a customary manner,e.g. while adding isotonizing agents, preservatives, such asp-hydroxybenzoates, or stabilizers, such as alkali metal salts ofethylenediaminetetraacetic acid, where appropriate using emulsifiersand/or dispersants, with it being possible, for example, to employ,where appropriate, organic solvents as solubilizing agents or auxiliarysolvents when using water as diluent, and aliquoted into injectionbottles or ampoules or infusion bottles.

The capsules, which comprise one or more active compounds or activecompound combinations, can, for example, be produced by mixing theactive compounds with inert carriers, such as lactose or sorbitol, andencapsulating the mixture in gelatine capsules. Suitable suppositoriescan be produced, for example, by mixing with excipients which areenvisaged for this purpose, such as neutral fats or polyethylene glycol,or their derivatives.

Auxiliary substances which may be mentioned by way of example are water,pharmaceutically unobjectionable organic solvents, such as paraffins(e.g. petroleum fractions), oils of vegetable origin (e.g. groundnut oilor sesame oil), monofunctional or polyfunctional alcohols (e.g. EtOH orglycerol), carrier substances such as natural mineral powders (e.g.kaolins, argillaceous earths, talc and chalk), synthetic mineral powders(e.g. highly disperse silicic acid and silicates), sugars (e.g. canesugar, lactose and grape sugar), emulsifiers (e.g. lignin, sulphitewaste liquors, methyl cellulose, starch and polyvinylpyrrolidone) andglidants (e.g. magnesium stearate, talc, stearic acid and sodium laurylsulphate).

Administration is effected in a customary manner, preferably orally ortransdermally, in particular and preferably orally. In the case of oraluse, the tablets can naturally also comprise, in addition to theabovementioned carrier substances, additives such as sodium citrate,calcium carbonate and dicalcium phosphate together with a variety offurther substances such as starch, preferably potato starch, gelatineand the like. It is furthermore also possible to use glidants, such asmagnesium stearate, sodium lauryl sulphate and talc, for the tableting.In the case of aqueous suspensions, a variety of taste improvers or dyescan also be added to the active compounds in addition to theabovementioned auxiliary substances.

For parenteral administration, it is possible to employ solutions of theactive compounds while using suitable liquid carrier materials. Thedosage for intravenous administration is 1-1000 mg per hour, preferablybetween 5 and 500 mg per hour.

Despite this, it may be necessary, where appropriate, to diverge fromthe abovementioned quantities, depending on the body weight or thenature of the route of administration, on the individual response to themedicament, on the nature of its formulation and on the time or intervalat which the administration is effected. Thus, it may, in some cases, besufficient to make do with less than the previously mentioned lowestquantity whereas, in other cases, the abovementioned upper limit has tobe exceeded. When relatively large quantities are being administered, itmay be advisable to divide these into several single doses which aregiven over the course of the day.

The following formulation examples illustrate the present inventionwithout, however, restricting its scope:

Pharmaceutical Formulation Examples

A) Tablets per tablet Active compound in accordance with formula (1) 100mg Lactose 140 mg Maize starch 240 mg Polyvinylpyrrolidone  15 mgMagnesium stearate  5 mg 500 mg

The finely ground active compound, lactose and a part of the maizestarch are mixed with each other. The mixture is sieved, after which itis moistened with a solution of polyvinylpyrrolidone in water, kneaded,wet-granulated and dried. The granular material, the remainder of themaize starch and the magnesium stearate are sieved and mixed with eachother. The mixture is pressed into tablets of suitable shape and size.

B) Tablets per tablet Active compound in accordance with formula (1) 80mg Lactose 55 mg Maize starch 190 mg  Microcrystalline cellulose 35 mgPolyvinylpyrrolidone 15 mg Sodium carboxymethyl starch 23 mg Magnesiumstearate  2 mg 400 mg 

The finely ground active compound, a part of the maize starch, thelactose, microcrystalline cellulose and polyvinylpyrrolidone are mixedwith each other, after which the mixture is sieved and worked, togetherwith the remainder of the maize starch and water, into a granularmaterial, which is dried and sieved. The sodium carboxymethyl starch andthe magnesium stearate are then added to the granular material and mixedwith it, and the mixture is pressed into tablets of suitable size.

C) Ampoule solution Active compound in accordance with formula (1) 50 mgSodium chloride 50 mg Water for injection  5 ml

The active compound is dissolved, either at its intrinsic pH or, whereappropriate, at pH 5.5-6.5, in water after which sodium chloride isadded as isotonizing agent. The resulting solution is renderedpyrogen-free by filtration and the filtrate is aliquoted, under asepticconditions, into ampoules, which are then sterilized and sealed bymelting. The ampoules contain 5 mg, 25 mg and 50 mg of active compound.

1. A compound of the formula (1),

wherein R¹ and R⁴ independently from one another denotes a groupselected from among R^(a), R^(b) and R^(a) substituted by one or moreidentical or different R^(b) and/or R^(c); or one R¹ together with thepyridine form a 9-10 membered heteroaryl ring, which is optionallysubstituted with one or more identical or different R^(b) and/or R^(c)and R² and R³ independently from one another denotes a group selectedfrom among C₁₋₆alkyl, C₃₋₈cycloalkyl, 3-8 membered heterocycloalkyl,C₆₋₁₀aryl and 5-12 membered heteroaryl, optionally substituted by one ormore identical or different R⁵ and each R⁵ denotes a group selected fromamong R^(a), R^(b) and R^(a) substituted by one or more identical ordifferent R^(b) and/or R^(c); and each R^(a) independently of oneanother denotes a group optionally substituted by one or more identicalor different R^(b) and/or R^(c), selected from among C₁₋₆alkyl, 2-6membered heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 memberedheteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, each R^(b)denotes a suitable group and is selected independently of one anotherfrom among ═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(c), ═NR^(c),═NOR^(c), ═NNR^(c)R^(c), ═NN(R^(g))C(O)NR^(c)R^(c), —NR^(c)R^(c),—ONR^(c)R^(c), —N(OR^(c))R^(c), —N(R^(g))NR^(c)R^(c), halogen, —CF₃,—CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(c), —S(O)OR^(c),—S(O)₂R^(c), —S(O)₂OR^(c), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c),—OS(O)R^(c), —OS(O)₂R^(c), —OS(O)₂OR^(c), —OS(O)NR^(c)R^(c),—OS(O)₂NR^(c)R^(c), —C(O)R^(c), —C(O)OR^(c), —C(O)SR^(c),—C(O)NR^(c)R^(c), —C(O)N(R^(g))NR^(c)R^(c), —C(O)N(R^(g))OR^(c),—C(NR^(g))NR^(c)R^(c), —C(NOH)R^(c), —C(NOH)NR^(c)R^(c), —OC(O)R^(c),—OC(O)OR^(c), —OC(O)SR^(c), —OC(O)NR^(c)R^(c), —OC(NR^(g))NR^(c)R^(c),—SC(O)R^(c), —SC(O)OR^(c), —SC(O)NR^(c)R^(c), —SC(NR^(g))NR^(c)R^(c),—N(R^(g))C(O)R^(c), —N[C(O)R^(C)]₂, —N(OR^(g))C(O)R^(c),—N(R^(g))C(NR^(g))R^(c), —N(R^(g))N(R^(g))C(O)R^(c),—N[C(O)R^(c)]NR^(c)R^(c), —N(R^(g))C(S)R^(c), —N(R^(g))S(O)R^(c),—N(R^(g))S(O)OR^(c), —N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)]₂,—N(R^(g))S(O)₂OR^(c), —N(R^(g))S(O)₂NR^(c)R^(c), —N(R^(g))[S(O)₂]₂R^(c),—N(R^(g))C(O)OR^(c), —N(R^(g))C(O)SR^(c), —N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(O)NR^(g)NR^(c)R^(c), —N(R^(g))N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(S)NR^(c)R^(c), —[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c),—N{[C(O)]₂R^(c)}₂, —N(R^(g))[C(O)]₂OR^(c), —N(R^(g))[C(O)]₂NR^(c)R^(c),—N{[C(O)]₂OR^(c)}₂, —N{[C(O)]₂NR^(c)R^(c)}₂, —[N(R^(g))C(O)]₂OR^(c),—N(R^(g))C(NR^(g))OR^(c), —N(R^(g))C(NOH)R^(c),—N(R^(g))C(NR^(g))SR^(c), —N(R^(g))C(NR^(g))NR^(c)R^(c) and—N═C(R^(g))NR^(c)R^(c) and each R^(c) independently of one anotherdenotes hydrogen or a group optionally substituted by one or moreidentical or different R^(d) and/or R^(e), selected from amongC₁₋₆alkyl, 2-6 membered heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 memberedhetero-aryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, and each R^(d)denotes a suitable group and is selected independently of one anotherfrom among ═O, —OR^(e), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(e), ═NR^(e),═NOR^(e), ═NNR^(e)R^(e), ═NN(R^(g))C(O)NR^(e)R^(e), —NR^(e)R^(e),—ONR^(e)R^(e), —N(R^(g))NR^(e)R^(e), halogen, —CF₃, —CN, —NC, —OCN,—SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(e), —S(O)OR^(e), —S(O)₂R^(e),—S(O)₂OR^(e), —S(O)NR^(e)R^(e), —S(O)₂NR^(e)R^(e), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)₂OR^(e), —OS(O)NR^(e)R^(e), —OS(O)₂NR^(e)R^(e),—C(O)R^(e), —C(O)OR^(e), —C(O)SR^(e), —C(O)NR^(e)R^(e),—C(O)N(R^(g))NR^(e)R^(e), —C(O)N(R^(g))OR^(e), —C(NR^(g))NR^(e)R^(e),—C(NOH)R^(e), —C(NOH)NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)SR^(e), —OC(O)NR^(e)R^(e), —OC(NR^(g))NR^(e)R^(e), —SC(O)R^(e),—SC(O)OR^(e), —SC(O)NR^(e)R^(e), —SC(NR^(g))NR^(e)R^(e),—N(R^(g))C(O)R^(e), —N[C(O)R^(e)]₂, —N(OR^(g))C(O)R^(e),—N(R^(g))C(NR^(g))R^(e), —N(R^(g))N(R^(g))C(O)R^(e),—N[C(O)R^(e)]NR^(e)R^(e), —N(R^(g))C(S)R^(e), —N(R^(g))S(O)R^(e),—N(R^(g))S(O)OR^(e)—N(R^(g))S(O)₂R^(e), —N[S(O)₂R^(e)]₂,—N(R^(g))S(O)₂OR^(e), —N(R^(g))S(O)₂NR^(e)R^(e), —N(R^(g))[S(O)₂]₂R^(e),—N(R^(g))C(O)OR^(e), —N(R^(g))C(O)SR^(e), —N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(O)NR^(g)NR^(e)R^(e), —N(R^(g))N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(S)NR^(e)R^(e), —[N(R^(g))C(O)]₂R^(e), —N(R^(g))[C(O)]₂R^(e),—N{[C(O)]₂R^(e)}₂, —N(R^(g))[C(O)]₂OR^(e), —N(R^(g))[C(O)]₂NR^(e)R^(e),—N{[C(O)]₂OR^(e)}₂, —N{[C(O)]₂NR^(e)R^(e)}₂, —[N(R^(g))C(O)]₂OR^(e),—N(R^(g))C(NR^(g))OR^(e), —N(R^(g))C(NOH)R^(e),—N(R^(g))C(NR^(g))SR^(e), —N(R^(g))C(NR^(g))NR^(e)R^(e) and—N═C(R^(g))NR^(e)R^(e) each R^(e) independently of one another denoteshydrogen or a group optionally substituted by one or more identical ordifferent R^(f) and/or R^(g), selected from among C₁₋₆alkyl, 2-6membered heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 memberedhetero-aryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl, and each R^(f)denotes a suitable group and in each case is selected independently ofone another from among ═O, —OR^(g), C₁₋₃haloalkyloxy, —OCF₃, ═S,—SR^(g), ═NR^(g), ═NOR^(g), ═NNR^(g)R^(g), ═NN(R^(h))C(O)NR^(g)R^(g),—NR^(g)R^(g), —ONR^(g)R^(g), —N(R^(h))NR^(g)R^(g), halogen, —CF₃, —CN,—NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(g), —S(O)OR^(g),—S(O)₂R^(g), —S(O)₂OR^(g), —S(O)NR^(g)R^(g), —S(O)₂NR^(g)R^(g),—OS(O)R^(g), —OS(O)₂R^(g), —OS(O)₂OR^(g), —OS(O)NR^(g)R^(g),—OS(O)₂NR^(g)R^(g), —C(O)R^(g), —C(O)OR^(g), —C(O)SR^(g),—C(O)NR^(g)R^(g), —C(O)N(R^(h))NR^(g)R^(g), —C(O)N(R^(h))OR^(g),—C(NR^(h))NR^(g)R^(g), —C(NOH)R^(g), —C(NOH)NR^(g)R^(g), —OC(O)R^(g),—OC(O)OR^(g), —OC(O)SR^(g), —OC(O)NR^(g)R^(g), —OC(NR^(h))NR^(g)R^(g),—SC(O)R^(g), —SC(O)OR^(g), —SC(O)NR^(g)R^(g), —SC(NR^(h))NR^(g)R^(g),—N(R^(h))C(O)R^(g), —N[C(O)R⁹]₂, —N(OR^(h))C(O)R^(g),—N(R^(h))C(NR^(h))R^(g), —N(R^(h))N(R^(h))C(O)R^(g),—N[C(O)R^(g)]NR^(g)R^(g), —N(R^(h))C(S)R^(g), —N(R^(h))S(O)R^(g),—N(R^(h))S(O)OR^(g), —N(R^(h))S(O)₂R^(g), —N[S(O)₂R^(g)]₂,—N(R^(h))S(O)₂OR^(g), —N(R^(h))S(O)₂NR^(g)R^(g), —N(R^(h))[S(O)₂]₂R^(g),—N(R^(h))C(O)OR^(g), —N(R^(h))C(O)SR^(g), —N(R^(h))C(O)NR^(g)R^(g),—N(R^(h))C(O)NR^(h)NR^(g)R^(g), —N(R^(h))N(R^(h))C(O)NR^(g)R^(g),—N(R^(h))C(S)NR^(g)R^(g), —[N(R^(h))C(O)]₂R^(g), —N(R^(h))[C(O)]₂R^(g),—N{[C(O)]₂R^(g)}₂, —N(R^(h))[C(O)]₂OR^(g), —N(R^(h))[C(O)]₂NR^(g)R^(g),—N{[C(O)]₂OR^(g)}₂, —N{[C(O)]₂NR^(g)R^(g)}₂, —[N(R^(h))C(O)]₂OR^(g),—N(R^(h))C(NR^(h))OR^(g), —N(R^(h))C(NOH)R^(g),—N(R^(h))C(NR^(h))SR^(g), —N(R^(h))C(NR^(h))NR^(g)R^(g); and—N═C(R^(h))NR^(h)R^(h); and each R^(g) independently of one anotherdenotes hydrogen or a group optionally substituted by one or moreidentical or different R^(h), selected from among C₁₋₆alkyl, 2-6membered heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 memberedhetero-aryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl; and each R^(h)is selected independently of one another from among hydrogen, C₁₋₆alkyl,2-6 membered heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 5-12 memberedheteroaryl, 6-18 membered heteroarylalkyl, 3-14 memberedheterocycloalkyl and 4-14 membered heterocycloalkylalkyl; and m denotes0, 1 or 2; and n denotes 0, 1, 2 or 3; and or a tautomer or saltthereof.
 2. A compound according to claim 1, wherein R³ denotesC₆₋₁₀aryl or 5-12 membered Heteroaryl, optionally substituted by one ormore identical or different R⁵.
 3. A compound according to claim 2,wherein R³ denotes phenyl, optionally substituted by one or moreidentical or different R⁵.
 4. A compounds according to claim 2, whereinR³ denotes pyridyl, optionally substituted by one or more identical ordifferent R⁵.
 5. A compound according to claim 2, wherein R³ denotespyrazolyl, optionally substituted by one or more identical or differentR⁵.
 6. A compound according to claim 1, wherein R² denotes methyl orethyl.
 7. A compound according to claim 1, wherein n denotes 1 or
 2. 8.A compound according to claim 1, wherein R¹ denotes methyl, ethyl, or—NR^(c)R^(c).
 9. A compound according to claim 1, wherein R¹ is —NH₂,—NH—CH₃ or —N(CH₃)₂.
 10. A compound according to claim 1, wherein R^(a)is hydrogen, methyl, ethyl or cyclopropyl.
 11. A compound according toclaim 1, wherein R^(b) is —F, —Cl, —CH₃, —OCH₃, —CF₃, —C(O)—R^(c),—C(O)NR^(c)R^(c), —C(O)OH, —C(O)OCH₃, —C(O)—NH₂, —C(O)—NHCH₃,—C(O)—N(CH₃)₂, —S(O)₂CH₃, or -2-propyl-R^(c).
 12. A compound accordingto claim 1, wherein R^(c) is —H, —CN, -methyl, -ethyl, —(CH₂)₂—OCH₃,piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl.
 13. A compoundaccording to claim 1, wherein R³ is phenyl substituted with one or moreR⁵, wherein at least one of R⁵ is —C(O)R^(c) and wherein R^(c) is


14. A compound according to claim 1, wherein R^(d) is —H, -methyl,-ethyl, -propyl, —OH, —OCH₃, or —C(O)CH₃.
 15. A compound according toclaim 1, wherein R^(e) is -cyclopropyl, cyclopentyl, oxiranyl,tetrahydropyranyl, or morpholinyl.
 16. A compound according to claim 1,wherein R³ is selected from the group consisting of


17. A compound selected from the group consisting of:2-{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-phenyl}-2-methyl-propionitrile,5-(2,2′-Diethyl-[4,4′]bipyridinyl-3-ylethynyl)-pyridin-2-ylamine,5-(2-Ethyl-2′,6′-dimethyl-[4,4′]bipyridinyl-3-ylethynyl)-pyridin-2-ylamine,5-(6-Cyclopropyl-2′-ethyl-[3,4′]bipyridinyl-3′-ylethynyl)-pyridin-2-ylamine,5-(2′-Ethyl-6-trifluoromethyl-[3,4′]bipyridinyl-3′-ylethynyl)-pyridin-2-ylamine,{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-morpholin-4-yl-methanone,{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-piperazin-1-yl-methanone,{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-(4-methyl-piperazin-1-yl)-methanone,{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-phenyl}-(4-methyl-piperazin-1-yl)-methanone,{4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-phenyl}-(4-methyl-piperazin-1-yl)-methanone,{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-methoxy-phenyl}-(4-methyl-piperazin-1-yl)-methanone,{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-(4-ethyl-piperazin-1-yl)-methanone,{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-phenyl}-(4-ethyl-piperazin-1-yl)-methanone,{4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-phenyl}-(4-ethyl-piperazin-1-yl)-methanone,{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-methoxy-phenyl}-(4-ethyl-piperazin-1-yl)-methanone,{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-(4-cyclopropyl-piperazin-1-yl)-methanone,{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-phenyl}-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-methanone,{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-phenyl}-(4-morpholin-4-yl-piperidin-1-yl)-methanone,{4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-phenyl}-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-methanone,1-(4-{4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoyl}-piperazin-1-yl)-ethanone,and4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-N-(2-methoxy-ethyl)-N-methyl-benzamide,or a salt thereof.
 18. A pharmaceutically acceptable salt of a compoundaccording to any one of claims 1 to
 17. 19. A pharmaceutical compositioncomprising a compound according to one of claims 1 to 17 or apharmaceutically acceptable salt thereof, in combination with a carrieror diluent.